Advances in Heterocyclic Chemistry, Volume 101

EDITORIAL ADVISORY BOARD A. T. Balaban, Galveston, Texas A. J. Boulton, Norwich, England D. Comins, North Caroline, United States of America J. Joule, Manchester, United Kingdom V. Minkin, Rostov-on-Don, Russia A. Padwa, Georgia, United States of America C. A. Ramsden, Keele, England E. F. V. Scriven, Trafalgar, Indiana V. Snieckus, Ontario, Canada B. Stanovnik, Ljubljana, Slovenia C. Stevens, Gent, Belgium R. Taylor, York, United Kingdom J. A. Zoltewicz, Gainesville, Florida

Advances in

HETEROCYCLIC CHEMISTRY VOLUME

101 Editor

ALAN R. KATRITZKY, FRS

Kenan Professor of Chemistry

Department of Chemistry

University of Florida

Gainesville, Florida

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CONTRIBUTORS

Numbers in parentheses indicate the pages on which the author’s

contribution begins.

David StC Black (97)

School of Chemistry, The University of New South Wales, UNSW

Sydney, NSW 2032, Australia

El Sayed H. El Ashry (161)

Chemistry Department, Faculty of Science, Alexandria University, Alex­ andria, Egypt; Fachbereich Chemie, Universitate Konstanz, D-78457 Kon­ stanz, Germany; and International Center for Chemical and Biological

Sciences, HEJ Research Institute of Chemistry, University of Karachi,

Karachi 75270, Pakistan

Yeldez El Kilany (161)

Chemistry Department, Faculty of Applied Sciences, Um-Alqura Univer­ sity, Makka, Saudi Arabia

Raymond C.F. Jones (125)

Department of Chemistry, Loughborough University, Loughborough,

Leicestershire LE11 3TU, UK

Rahul D. Kavthe (75)

Organic Chemistry Division II, Indian Institute of Chemical Technology,

Hyderabad 500 607, India

Naresh Kumar (97)

School of Chemistry, The University of New South Wales, UNSW

Sydney, NSW 2032, Australia

Charles N. Moorefield (1)

Maurice Morton Institute for Polymer Science, The University of Akron,

Akron, OH 44325, USA

vii

viii

Contributors

Said Nadeem (161)

International Center for Chemical and Biological Sciences, HEJ Research

Institute of Chemistry, University of Karachi, Karachi 75270, Pakistan

George R. Newkome (1)

Departments of Polymer Science and Chemistry, The University of

Akron, Akron, OH 44325-4717, USA and Maurice Morton Institute for

Polymer Science, The University of Akron, Akron, OH 44325, USA

Nitin T. Patil (75)

Organic Chemistry Division II, Indian Institute of Chemical Technology,

Hyderabad 500 607, India

Muhammad Raza Shah (161)

International Center for Chemical and Biological Sciences, HEJ Research

Institute of Chemistry, University of Karachi, Karachi 75270, Pakistan

Monica Soler (1)

Departments of Polymer Science and Chemistry, The University of

Akron, Akron, OH 44325-4717, USA

Yoshinori Yamamoto (75)

WPI-AIMR (Advanced Institute for Materials Research), Tohoku Univer­ sity, Katahira 2-1-1, Aobaku, Sendai 980-8577, Japan and Department of

Chemistry, Graduate School of Science, Tohoku University, Aramaki,

Aobaku, Sendai 980-8578, Japan

MILESTONE OF 100 VOLUMES OF ADVANCES IN HETEROCYCLIC CHEMISTRY MARKED BY THE PUBLICATION OF VOLUMES 99, 100, AND 101 AS A CELEBRATORY SET

It is hard to believe that it is now 50 years since I conceived the concept of periodical volumes of these “Advances” that would record progress in Heterocyclic Chemistry. In 1960, heterocyclic chemistry was slowly emer­ ging from the dark ages; chemists still depicted purines by the archaic structural designation introduced (was it by Emil Fischer?) 50 years before that. Together with Jeanne Lagowski I had published in 1959 a modern text on heterocyclic chemistry, the first that treated this subject in terms of structure and mechanism and attempted to logically cover sig­ nificant methods of preparation and reactions of heterocyclic compounds as a whole, all in terms of reactivity. The first two volumes of Advances contained extensive chapters on the tautomerism of various classes of heterocycles. Despite the great influence the precise structure of heterocyclic compounds has on chemi­ cal and biological properties (we only have to remember base pairing of nucleotides to illustrate this), at that time the literature was replete with incorrectly depicted tautomers. The basis for the position of tautomeric equilibria was usually completely misunderstood. Although great pro­ gress has been made in the last 50 years, there still exist holdouts even among otherwise reputable chemists who persist in depicting 2-pyridone as ‘‘2-hydroxypyridine’’ which is a very minor component of the tauto­ meric equilibrium under almost all conditions. Over the years Advances in Heterocyclic Chemistry has indeed mon­ itored many of the advances in the subject: the series is now boosted by “Comprehensive Heterocyclic Chemistry” of which the first edition was published in 1984 in 8 volumes, followed by the second edition in 1996 in 11 volumes and the third in 2008 in 15 volumes. Heterocyclic chemistry

ix

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Milestone of 100 Volumes of Advances in Heterocyclic Chemistry

has now taken its place as one of the major branches (by several criteria the most important) of Organic Chemistry. Chemistry has rapidly become the universal language of molecular interactions; it has essentially taken over biochemistry and is rapidly gaining dominance in zoology, botany, physiology and indeed in many branches of medicine. Chemical structural formulae are quite basic to this progress and have enabled us to rationalize many natural phenomenon and countless reactions both simple and exotic discovered in the laboratory. Now we have reached the milestone of 100 volumes of the series. In place of a single volume we are offering the three volume set 99, 100 and 101 which contain a fascinating variety of reviews covering exciting topics in heterocyclic chemistry. Alan R. Katritzky Gainesville, Florida

PREFACE TO VOLUME 101

The final volume celebrating the attainment of the century for AHC contains five chapters contributed by heterocyclic chemists from six countries. Soler, Moorefield, and Newkome (U. Akron, Akron, OH, USA) start with a fascinating account of the Senior Author’s work on the construc­ tion of hexameric macromolecular architectures in organic chemistry. Patil, Kavthe, and Yamamoto (I.I.C.T., Hyderabad, India, and Tohoku U., Japan) summarize metal catalyzed cyclizations of alkynes bearing a heteroatom attached to a substituent which migrates during the annulation. The chemistry of the 28 possible isomeric biindolyl structures is cov­ ered by Black and Kumar (UNSW, Sydney, Australia), while R.C.F. Jones (Loughborough U., Loughborough, UK) has reviewed his own and others’ research on annulation reactions of 2-imidazoline. The volume closes with an upto date account of the chemistry of the Dimroth Rear­ rangement contributed by E.S.H. El Ashry, S. Nadeem, M.R. Shah, and Y.E. Kilany of Alexandria U. in Egypt. Alan R. Katritzky Gainesville, Florida

xi

CHAPTER

1 Hexameric Macrocyclic Architectures in Heterocyclic Chemistry Monica Soler,a Charles N. Moorefieldb and George R. Newkomea,b

Contents

1. Introduction 2. Macrocycles with Five-Membered Heterocyclic Subunits 2.1 Furan, tetrahydrofuran, and thiophene 2.2 Pyrrole 2.3 Cucurbituril 2.4 Cyclofructans 2.5 Diazole 3. Six-Membered Ring Heterocycles 3.1 Pyridine 3.2 Pyrimidine 3.3 Phenanthroline 3.4 Oligosaccharides 4. Miscellaneous Heterocyclic Materials 4.1 Flexible rings 4.2 Terpyridine and phenanthroline 4.3 Five- and six-membered 4.4 Nucleobases, nucleosides, and nucleotides 5. Conclusions References

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a

Departments of Polymer Science and Chemistry, The University of Akron, Akron, OH 44325-4717, USA

b

Maurice Morton Institute for Polymer Science, The University of Akron, Akron, OH 44325, USA

Advances in Heterocyclic Chemistry, Volume 101 ISSN 0065-2725, DOI 10.1016/S0065-2725(10)01001-9


2010 Elsevier Inc. All rights reserved

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Monica Soler et al.

1. INTRODUCTION Peter Stang once noted (97JA4777) that “In nature the hexagon represents the most common pattern throughout biological morphology from the simple diatoms to the bee honeycomb” after reading a treatise by Geof­ frey Ozin (97ACR17) describing his investigations into the morphosynth­ esis of hierarchical inorganic structures, such as that of the radiolaria. The ubiquitous occurrence of the hexagonal motif in nature coupled with Peter Pearce’s postulate (78MI1) that “structure in nature is a strategy for design” provides insight and reason to the plethora of diverse hex­ agonal architectures formed throughout synthetic chemistry. As well, the burgeoning arena of Supramolecular Chemistry, pioneered by Jean-Marie Lehn (78PAC871, 88AGE89, 95MI1), expands the platform for access to self-assembled macrocycles based on the attractive interactions between select metal ions and structurally compatible heterocyclic ligands. Trans­ cending consideration of covalent versus non-covalent bonding, supra­ molecular chemistry considers building blocks instilled with angles, coordination sites, and affinities that drive their assembly to architectures with utilities and designs not accessed from the starting materials alone. Conjointment of the supramolecular regime with directed and conver­ gent synthetic protocols has facilitated new routes to macrocyclic structures. In a seminal review of the field of self-assembly of architectures mediated by transition metals Stang et al. (00CRV853) discussed and delineated design strategies or models developed over the years by such notable scientists as Saalfrank (97AGE2482), Lehn (99CEJ102, 99CEJ113), Raymond (99ACR975) [“Symmetry Interaction” Model], Ver­ kade (83JA2494), Fujita (98CSR417), and Stang (97ACR502, 98JCD1707) [“Molecular Library Model”]. The Symmetry Interaction model considers the geometric relationships between ligand coordination sites and metal centers by defining chelate or coordinate vectors, based on the directional orientation of the ligandbinding sites. For example, a bidentate bipyridine ligand coordinated to a metal possesses a vector pointing toward the metal that bisects the chelating group. The Molecular Library model considers the directionality and geometry of multibranched, monodentate ligands and their ramifications on the geometry of the desired molecular architecture. For example, rod­ like building blocks with incorporated angles of 90 and end-group coordination sites would generate a tetragonal shape in the presence of a connecting metal that is capable of sustaining 90 coordination. Herein, we present a brief overview of the current literature dedicated to hexameric macrocyclic architectures predicated on heterocyclic chem­ istry. We summarize the salient synthetic features of ring construction whereby the participating heterocyclic building blocks, or subunits,

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

3

possessing at least one heteroatom, such as nitrogen, oxygen, or sulfur, with the recognition that such a broad subject will necessitate a limitation in scope. Excluding the “Introduction,” this review is organized based on the building blocks used for macrocycle construction into three sections: fivemembered heterocyclic subunits, such as furan, furanose, or pyrole; six-membered heterocyclic subunits, such as pyridine, bipyridine, phenan­ throline, or glucopyranose; and miscellaneous subunits comprising, for example, a combination of five- and six-membered heterocyclic subunits or larger than six-membered ring subunits. We have sought to include as many pertinent new and classical examples as possible and will endeavor to include examples that have been missed in future manuscripts.

2. MACROCYCLES WITH FIVE-MEMBERED HETEROCYCLIC SUBUNITS 2.1 Furan, tetrahydrofuran, and thiophene Hexameric macrocycles possessing subunits with oxygen have been reported, of which some of the earliest examples incorporated a series of 18-crown-6 ethers containing one-, two-, or three-furanyl subunits (74JA7159). In 1955, Wright et al. reported (55JOC1147) the first example of calix[6]furan 1, comprising six furan rings joined by sp3-hybridized carbons. Such calix[6]furans possess a p-electron-rich cavity with a hydrophilic character similar to crown ethers, but with decreased elec­ tron-donating character compared with ethereal analogues (05AHC65). The calix[6]furan 1, which contains methyl groups in the meso-positions, was synthesized following a two-step procedure involving the formation of a three-furan linear oligomer by an acid-catalyzed condensation of furan and acetone. Once the linear trimer was isolated, cyclization was achieved by reaction with acetone in the presence of hydrochloric acid affording (9%) the heterocycle 1 along with linear oligomers (Scheme 1). Kobuke et al. (76JA7414) modified the procedure for 1 by bubbling hydrogen chloride gas into a solution of acetone and linear hexamer to afford 1 in 52% yield. Other modified procedures include the addition of concentrated HCl, acetone, and linear hexamer in ethanol containing Liþ or Csþ ions or no metal, which afforded 1 in ~50% yields (85JCS(P1)973), or slow addition of linear trimer and acetone to a diluted EtOH/HCl mixture with 25% yield (96TL4593). Musau et al. reported (93CC1029, 94JCS(P1)2881) the synthesis of the calix[6]furan with unsubstituted methylene bridges, by cyclization of the corresponding linear hexamer using dimethoxymethane, in the presence of BF3Et2O, as the catalyst; however, the desired hexamer was isolated in ~1% yield. Kobuke et al.

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Monica Soler et al.

Scheme 1

(76JA7414) also reported the tetrahydrofuran analogue (Scheme 1) by the hydrogenation of the furan units of 1 using ruthenium/carbon under high pressure conditions to generate an isomeric mixture of the hexamer 2, which was shown to extract cesium, ammonium, and silver ions from an aqueous to an organic phase. Finally, a larger hexameric macrocycle containing six furan rings joined via acetylene bridges was also reported (69AJC1951). Three examples of hexameric macrocycles containing thiophene rings have been reported. Meijere et al. described (95AGE781) the novel macrocycle 4, composed of six thiophene rings linked via spirocyclopropane bridges. Reaction of polyalkyne 3 with Na2S under basic conditions afforded within an hour 4, which was isolated by recrystallization in chloroform in 59% yield (Scheme 2). The crystal structure (Figure 1) showed a chair-like conformation, in which three sulfur atoms are above and three below the plane of the macrocycle.

Scheme 2

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

Figure 1 VCH).

5

X-ray crystal structure of 4 (95AGE781) (Reproduced by permission from Wiley-

Ishii et al. (97CL897, 98BCJ2695) synthesized a sulfur-bridged thio­ phene macrocycle 5. Several different conditions were examined for the preparation of 5 from different oligomers; the best results were obtained (~10%) by heating dibromo oligo(thio-2,5-thienylene) containing six thiophene rings with Na2S in NMP in the presence of Cs2CO3 (Scheme 3). Conditions such as CuI-catalyzed or non-catalyzed reactions also gave the desired product, albeit in slightly lower yields. Sulfur-bridged calix­ arene-like molecules could function as hosts to soft and heavy metal ion guests. Another example of a cyclohexathiophene was reported by Kauff­ mann et al. (75AGE713), composed of six thiophene subunits bound together through the 2,20 - and 3,30 -positions. It was isolated as a by­ product in 4% yield, not completely purified, from the reaction designed to obtain cyclotetrathiophene. Jones et al. (95AGE661) reported the synthesis of silicon-bridged heterocycles containing furan or thiophene subunits. Furan and thio­ phene were deprotonated at the 2- and 5-positions in hexane, to generate

Scheme 3

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Monica Soler et al.

Scheme 4

the organolithium intermediates, followed by slow addition of Me2SiCl2 to afford the cyclic hexamer 6 or 7 (Scheme 4), respectively, along with their corresponding cyclic tetramers. Macrocycles comprising other ring sizes were detected in trace amounts by mass spectrometry.

2.2 Pyrrole Examples of hexameric macrocycles containing pyrrole rings reported in the literature (01CCR57, 08ACR265) include hexaphyrins or expanded porphyrins, calix[6]pyrroles, and cyclo[6]pyrroles. Hexaphyrins are conjugated macrocycles composed of six pyrrole rings linked via sp2 hybridized carbon atoms. The first example, meso­ hexaphenylhexaphyrin (9), was prepared by Bruckner et al. (97CC1689) employing 5,10-diphenyltripyrrane (8) (Scheme 5), which was isolated as a by-product from a reaction designed to generate 5-phenyldipyrro­ methane, by the condensation of pyrrole and benzaldehyde in the pre­ sence of an acid (94T11427, 94TL2455, 94TL6823). A 3 þ 3-type condensation of trimer 8 with benzaldehyde, gave after oxidation and chromatography, the cyclic hexamer 5. A similar example,

Scheme 5

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

7

Scheme 6

meso-hexa(pentafluorophenyl)hexaphyrins, was reported by Cavaleiro et al. (99CC385) using a modification of the Rothemund synthesis (39JA2912). Calix[6]pyrroles are nonconjugated macrocycles composed of six pyr­ role rings linked via sp3 hybridized carbon atoms. A simple and efficient route to calix[6]pyrrole (98AGE2475) involved an acid-catalyzed conden­ sation of dipyrrolemethane with simple ketones that afforded polypyr­ role 10 (Scheme 6). X-ray structure determination of 10 revealed that pyrrole units adopted a 1,3,5-alternate conformation in contrast to the more prevalent cone conformation found in calix[6]arenes. Another example in this family was reported by Sessler et al. (05JOC5982), whereby the dodecafluorocalix[6]pyrrole 11 was con­ structed (20%) by the condensation of 3,4-difluoro-1H-pyrrole with acet­ one in the presence of methanesulfonic acid and tetrabutylammonium chloride (Scheme 7). Calix[6]pyrroles have also been synthesized (00AGE1496) by the con­ version of a calix[6]furan to form the dodecaketone 12 via a ring-opening process, as described by Williams and Le Goff (81JOC4143). Subsequent reduction of the olefinic bonds and reaction with ammonium acetate gave 13 in 42% yield (Scheme 8).

Scheme 7

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Monica Soler et al.

Scheme 8

Host-guest chemistry of calixpyrroles has become an important area of research. Compared to calix[4]pyrroles, which exhibit remarkable selectivity for binding fluoride (96JA5140), calix[6]pyrroles have been shown (01CC13) to form strong complexes with iodine. Other halide ions have shown (00CC1207) strong affinities to trihaloalkanes, such as trifluoroethanol, and electron-deficient aromatic systems, such as nitro­ benzene or p-nitrotoluene. Finally, cyclo[6]pyrroles are conjugated pyrrole-based macrocycles that contain no meso-carbon bridge. Sessler et al. reported (03JA6872) the preparation of the cyclo[6]pyrrole 14 [HCl salt of [22]hexaphyrin (0.0.0.0.0.0)] (15%) by coupling 3,30 ,4,40 -tetraalkylbipyrroles under bipha­ sic oxidative conditions (Scheme 9); cyclo[7]pyrrole and cyclo[8]pyrrole were also isolated. Two crystal structures of 14 were also reported, one containing two TFA2 ions (Figure 2) and the other two chloride ions. Later, the uranyl cationic complex of 14 was obtained by treatment with UO2[N(SiMe3)2]2 in CH2Cl2 under an inert atmosphere (07IC5143). Notably, during this insertion and oxidation process, the initial aromatic ring containing 22 p-electrons was transformed to the 20 p-electron antiaromatic heterocycle.

Scheme 9

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

9

Figure 2 X-ray crystal structure of H2142þ2TFA2, showing top and side views (03JA6872) (Reproduced by permission from American Chemical Society).

2.2.1 Porphyrin Based on their natural occurrence, physicochemical properties, potential to coordinate numerous metals, and access from readily available starting materials, porphyrins provide ideal building blocks for more complex architectures. Numerous researchers have studied these fascinating mate­ rials (09ACR1193, 09CCR2036, 09CSR422, 09CSR2716, 10CCR77). Anderson and Sanders (89CC1714) have reported the preparation of an hexameric porphyrin-trimer to accommodate organic guests. This cyclic trimer 16a was synthesized starting from a bis-acetylenic porphyrin, obtained by reaction of 3-ethynylbenzaldehyde with 3,30 -diethyl-4,40 -dimethyldipyrromethane, followed by oxidation of the porphyrinogen intermediate with DDQ (81JOC4792, 95JCS(P1)2223). A cyclic Glaser coupling of the bis-acetylenic porphyrin Zn adduct 15a using excess copper(I) chloride in pyridine at 25C with air afforded the cyclic trimer 16a (47%), after removing Zn with a dilute acid, along with the cyclic tetramer (20%), cyclic pentamer (traces), and insoluble cyclic dimer (Scheme 10). Addition of 2,4,6-tris-4-pyridyl-s-triazine (17) to the metallated 16a formed complex 18a, suggesting that 17 had a complemen­ tary shape for the cavity of the host 16a. Approximately 1 year later, the same group published (90AGE1400) a ligand-templated synthesis (93ACR469) of the cyclic trimer (16b) using tripyridine 17, as a template for directing the assembly, which gave, 16b in 55% yield (Scheme 10, dash line). The dramatic template effect observed with 17 enhanced the forma­ tion of the cyclic trimer 16b by inhibiting formation of the related dimer. The crystal structure of the porphyrin-trimer Zn adduct of 16a with three coordinated pyridines to the three Zn ions is presented in Figure 3. It ˚ revealed an open, flexible cavity with a mean Zn—Zn distance of ~16 A

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Monica Soler et al.

Scheme 10

(a)

(b)

Figure 3 (a) X-ray crystal structure of the porphyrin-trimer Zn adduct 16a with three coordinated pyridine ligands (94AGE429) (Reproduced by permission from Wiley VCH) and (b) drawing of the Zn adduct of the platinum-linked cyclic porphyrin-trimer 19.

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

11

(94AGE429). Another example of a cyclic porphyrin-trimer designed by Sanders et al. (92CC43), with the same topology as 16a but with a larger ˚ cavity, was presented by the platinum-linked cyclic porphyrin-trimer 18 A 19. Condensation of trans-[Pt(PEt3)2Cl2] and 15a with deoxygenated 10% (v/v) diethylamine in toluene, using Hagihara coupling conditions (78OMC319) with CuI as a catalyst, afforded 19 in 16% yield (drawing Figure 3b), together with expected intermediates. Attempts to increase the yield by templating with (Pyacac)3Al gave no significant improvement. Sanders et al. (95JCS(P1)2275) further reported the preparation of a cyclic porphyrin-trimer with an increased cavity size using octatetrayne bridges instead of butadiyne bridges. Sanders et al. also described (03CEJ5211) the formation of a hexameric macrocycle containing three Sn(IV) porphyrins with axial carboxylate ligands generated from the Sn(IV) dihydroxo derivatives, to study the ligand-recognition properties of tin(IV) porphyrins. Tin ion insertion into the cyclic trimer 16b was performed by refluxing anhydrous tin(II) dichloride in pyridine for 2 h, followed by the quantitative hydrolysis (passing the sample through a weak anion-exchange resin in a waterchloroform mixture) to afford, after recrystallization, trimetallated 20 in 28% yield (Scheme 11). Aliquots of carboxylic acids were then added to 20 in order to study the NMR properties of 21a and 21b. A more versatile linear synthesis allowed access to unsymmetrical cyclic trimers with different bridge lengths (ethyne and butadiyne links) (98NJC493) or mixed-metal trimers (97IC6117, 00IC5912). In 1999, two other cyclic porphyrin families were reported contain­ ing six-porphyrin subunits resembling that of the light harvesting supramolecular architectures in photosynthetic bacteria (95NAT517, 96ACR381). Dossauer et al. reported (99TL8347, 01JOC4973, 06JA3396) the construction of the rigid hexameric macrocycle 25, containing six tetra­ phenyl-porphyrin rings linked by six meta-diethynylphenyl corners, thus forming an internal cavity of 4.6 nm of diameter. The step-by-step method

Scheme 11

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Monica Soler et al.

Scheme 12

developed by this work enabled the synthesis of these macrocycles with different metallation “‘states’,” composed of a combination of Zn porphyrin (PZn), Ni porphyrin (PNi), and/or free-base porphyrins (PFB). The syn­ thetic procedure (Scheme 12) started with the reaction of the diiodopor­ phyrin derivative 22 with 23, affording a monomeric porphyrin-building block 24b, with two reactive positions, a protected ethynyl group and a diethyltriazine-substituted phenyl, which could be activated selectively. Employing an interactive divergent—convergent approach (94JA4227, 94AGE1360) to generate the linear precursor, the intramolecular cyclization was effected by a high-dilution, Pd(0)-mediated reaction. The final ringclosure step was the least reproducible affording after chromatographic purification, the product with variable yields (8—31%). Template synthesis of 25 was also attempted (06JA3396), where the yield of the cyclization of the linear precursor was improved to a reproducible yield (52—57%).

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

13

At about the same time, Lindsey et al. (99JA8927) described the one­ flask synthesis of a different family of cyclic hexamers, containing six porphyrins bridged by diphenylethynes. They also synthesized macrocycles with different degrees-of-metallation: one example with six PZn’s, and another with an alternating arrangement of three Zn or Mg porphyrins (PZn, PMg) and three free-base porphyrins (PFB). Macrocycle 29 was constructed (Scheme 13) by a Pd-mediated coupling of a Zn-metallated bis(4­ ethynylphenyl)porphyrin 26 with metal-free bis(3-iodophenyl)porphyrin 27 in the presence of a tripyridinyl template 28 affording 5.3% yield after purification (Scheme 13). Treatment of 29 with zinc acetate afforded the all­ metallated polyporphyrin 30 that was isolated in 94% yield. Two years later, (01JOC7402) this family of hexameric architectures was extended with the addition of two more examples, comprising five PZn and one PFB as well as comprising alternating sequence of two PZn and one PFB. Synthesis of these new additions did not follow the oneflask template-directed process, but was achieved by sequential Pd­ mediated coupling reactions involving four tetraarylporphyrin-building

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Monica Soler et al.

Scheme 13

blocks bearing diethynyl, diiodo, bromo/iodo, or iodo/ethynyl groups. The final ring-closure yielding the cyclic construct was performed by the reaction of a porphyrin pentamer and a porphyrin monomer or by joining two porphyrin trimers in the presence of a template. Linsey et al. (03JOC8199) later expanded this family of shape-persistent materials, by generating new derivatives bearing diverse pendant groups, such as thiol moieties, that were used to form self-assembled monolayers (SAMs). Char­ acterization by high-angle X-ray scattering of a host—guest complex with a tripyridyl guest has been reported (04JA14054). The structures of the light-harvesting complexes (LH) in photosyn­ thetic purple bacteria had been determined by X-ray crystallography studies, electron microscopies, and other analytical methods (95NAT517, 96MI1, 96MI2, 98JMB833, 01B8783). In these complexes, the bacteriochlorophylls (32 in LH1 and 16 in LH2) are arranged in macroring structures, where the key functional unit is composed of bacteriochlor­ ophyll-a dimers, which have been described as having a slipped-cofacial juxtaposition, held together by intermolecular forces, specifically the coordination of imidazolyl to the central Mg ion (03JA2372, 03OL4935, 05JOC2745). Kobuke et al. reported (03JA2372) the first example of a hexameric macrocycle 32 composed of six 5,50 -m-phenylene-bridged imi­ dazolylporphyrinatozinc(II) dimers (31), where coordination of the imida­ zolyl of one dimer to the zinc of the neighboring one closes the macrocycle. Synthesis of 31 started with the acid-catalyzed condensation

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

15

of meso-(n-heptyl)dipyrromethane with two aldehydes (isophthalalde­ hyde and 1-methyl-2-imidazolecarbaldehyde), followed by oxidation, which gave a mixture of porphyrin products. Column chromatography afforded 5,50 -m-phenylene-bridged gable-porphyrin with 15,150 -bis(imida­ zolyl) groups (31) (85JA4192) (Scheme 14) and other products. Addition of zinc acetate converted the free base 31 to polymeric assemblies, which after a reorganization process by cleavage of the coordination bonds upon dilution in more polar solvent (mixture of CHCl3/MeOH), followed by evaporation, afforded a mixture of two components, showing the disap­ pearance of almost all the oligomers. Once these two products were separated, analysis of the first one by small-angle X-ray scattering (SAXS) measurement concluded that it was the hexameric macrocycle 32. To further increase the stability, the macrocycle was covalently bound by an olefin metathesis of the allyloxypropyl substituents (the pendant groups in the meso-position of the porphyrin rings) in each dimer (03OL4935) (Scheme 15). This reaction was used to connect each pair of complementary coordinated porphyrins to the other pair. These macrocycles were analyzed by MALDI-TOF MS identifying the hexamer, along with a pentamer. Previous macrocycles containing gable-porphyrins (32–34) showed no p-conjugation between porphyrins since the porphyrin and phenylene planes were orthogonal. In an effort to introduce or increase conjugation,

Scheme 14

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Monica Soler et al.

Scheme 15

Kobuke et al. (06JA4612) also reported the synthesis of macrocycles using bis(zinc-imidazolylporphyrin) linked by a m-bis(ethynyl)phenylene spacer, allowing enhanced rotation along the ethyne axis. A different structure was formed when the repeat unit in the macrocycle was a trimer of porphyrin units instead of a dimer as seen with the gable­ porphyrins. Kobuke et al. reported (04JA8668) the hexameric macrocycle 36, which consisted of three porphyrin-trimer units, containing only nine porphyrin rings instead of twelve as in the precious macrocycles (Scheme 16). The free-base porphyrin-trimer 35 was synthesized by con­ densation of 5-(1-methylimidazol-2-yl)-10,15-bis(3-allyloxypropyl)-20-(3­ formylphenyl)porphyrin with meso-methoxycarbonyldipyrromethane in 20% yield. Metallation by addition of Zn(OAc)2 and reorganization using MeOH/CHCl3 mixtures afforded the cyclic hexamer 36. The two terminal porphyrins of each trimer in the hexamer helped in ring formation by coordination to the Zn ions of the terminal imidazole of the other trimer, leaving three noncoordinated porphyrinato-Zn(II) sites that could accom­ modate a functional molecule. 1H NMR spectra of 36 revealed a mixture of two topological isomers, D3h-symmetric (36a) and D3h-asymmetric (36b). Anderson et al. reported (08AGE4993) an efficient synthesis of strained, p-conjugated D6h porphyrin[6]nanoring 39. A template-directed reaction between the porphyrin dimer 37 and the hexapyridinyl template 38 by an oxidative coupling of 37 under palladium/copper catalysis, using iodine and air, as the oxidants, afforded the cyclic hexamer-tem­ plated complex 39 in 30—40% yield (Scheme 17). Size-exclusion chromato­ graphy in the presence of 1,4-diazabicyclo[2,2,2]octane gave the template­

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

Scheme 16

Scheme 17

17

18

Monica Soler et al.

free hexameric macrocycles 39 in high yields. Comparison between 39 and a similar linear hexamer showed that the p-conjugation was more effective in the macrocycle, probably because of the rigid geometry and lack of endeffects, as well as other contributions. Other interesting polyporphyrins have been reported by Osuka et al. (01CEJ3134). Two linear arrays of three porphyrin each, described as windmill arrays, were connected by a meso-meso-linked diporphyrin core and examined as light-harvesting devices.

2.2.2 Dipyrrin In contrast to having porphyrin units in the macrocycle, the use of dipyr­ rins (dipyrromethenes) (07CEJ7900) can afford flexible metal coordination environments. Dipyrrins (e.g., 40; Figure 4) (06JA10024) consist of two pyrrole units bridged by a sp2-meso carbon, behaving as a p-conjugated bidentate monoanionic ligand for metal ions, similar to a half-porphyrin unit. Hashimoto et al. reported (07CEJ7900) a family of neutral hexameric architectures composed of two dipyrrin ligands coordinated to two zinc ions forming a hexameric macrocycle in shape. Dipyrrin 40 (03IC6629) was synthesized by a Sonogashira coupling reaction (75TL4467) of 1,3­ diethynylbenzene and 3-bromobenzaldehyde, followed by acidic conden­ sation with pyrrole and finally oxidation with DDQ. Refluxing 40 with Zn (OAc)2 in the presence of pyrene, as a templating specie, in chloroform afforded 41 in good yield. Due to the tetrahedral geometry of the Zn(II) ions, complex 41 exhibits two chiral centers and three stereoisomers (one achiral and two chiral), where the chiral isomers are the minor species. The X-ray crystal structure of the major stereoisomer of 40 (Figure 4) showed a distorted hexagonal cavity with a 1.6-nm diagonal, with two THF solvent molecules encapsulated.

2.3 Cucurbituril Cucurbituril (42) is a cyclic hexamer of dimethanoglycoluril (81JA7367) synthesized from the acidic condensation of glycoluril and excess for­ maldehyde (Scheme 18a). It was first mentioned in 1905 by Behrend et al. (05LAC1), but it was not until 1981 when Mock et al. (81JA7367) fully characterized its chemical structure and coined the term “Cucurbituril” based on its resemblance to a pumpkin (family Cucurbitaceae). The ˚ hexamer 42 (Scheme 18b) possesses an internal cavity diameter of 5.5 A within the relatively rigid macrocycle to which access is provided by two ˚ diameter. Extensive studies entrances ringed by carbonyl groups of 4 A on the host—guest behavior of 20 have been published by Mock et al. and others (96CSMC477, 96JA9790, 02CSR96). Due to its unique structure and molecular recognition properties, cucurbituril (20) has been used in

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

N R

N

N R

R

19

N R

40 R = H, CH3 or C16H33

41

Figure 4 X-ray crystal structure of 41 (07CEJ7900) (reproduced by permission from Wiley-VCH) and the dipyrin 40 used in its construction.

numerous supramolecular architectures, as building blocks in rotaxanes, catenanes, or molecular machines (00IEC3419, 02CSR96). Other appli­ cations such as catalysis have been demonstrated (89JOC5302, 07CSR267). Scheme 18c illustrates an example of a polyrotaxane net­ work consisting of edge-sharing hexagons, having a silver ion at each corner. Each edge is holding a cucurbituril macrocycle (00IEC3419). Miyahara et al. reported (04AGE5019) a variation of the cucurbi­ turil (42), where the glycoluril unit was equatorially cut-in-half, giv­ ing rise to the name hemicucurbituril (43). Synthesis was achieved (94%) by the acid-catalyzed condensation of ethyleneurea with for­ maldehyde. The X-ray crystal structure (Figure 5) shows that 43 assumes an alternate conformation of the heterocyclic subunits and contains a chloride ion in the center of the cavity, H-bonded to a H2O molecule, which in turn is H-bonded to an external H2O mole­ cule, thus creating a rigid hydrogen-bonded network. Along with anions, 43 can also include small molecules, such as propargyl alcohol.

2.4 Cyclofructans Cyclofructans (94JOC2967) are cyclic oligosaccharides with five-mem­ bered ring heterocycles [b-(2!1)-linked-D-fructofuranose units] obtained from inulin with inulin fructotransferase, which catalyzes the formation

20

Monica Soler et al.

Scheme 18

(a)

(b)

Figure 5 a) X-ray crystal structure of 43 (04AGE5019) containing in the cavity (a) HCl and (b) propargyl alcohol (reproduced by permission from Wiley-VCH).

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

21

of the cycloinulohexaose (44), cycloinuloheptaose, and cycloinulooctaose. The former 44 displayed a hexameric architecture with a crown ether (18-crown-6) skeleton, which was expected to bind cationic molecules. Several complexation studies have been reported on permethylated cycloinulohexaose 45 in organic solvents (93CC53, 94JOC2967, 01JCS(P2)1306). Permethylated cycloinulohexaose 45 was synthesized fol­ lowing the Hakomori method (64JBT205, 86CAR279, 94JOC2967) starting from dimethylsulfinyl carbanion (Corey’s base), prepared from DMSO and NaH. A slight excess of dimethylsulfinyl carbanion was added to 44 in DMSO under N2, followed by slow addition of methyl iodide to afford 45 in 50% yield (Scheme 19). Complexation studies with 45 revealed lower alkali metal affinities than 18-crown-6 but still possessed the ability to capture Kþ and Ba2þ ions by a pocket constructed between the upper MeO-3 rim of the furanose rings and crown ether oxygens.

2.5 Diazole Two examples of metallomacrocycles containing diazole ligands are noted, a pyrazole- and an imidazole-derivative. Cohen et al. reported (03CC1278) the construction and crystal structure (Figure 6a) of [(5-methyl-3-phenylpyrazo­ le)2Zn2(O(CH2)2S)]6 (46), which was first isolated from thermal decomposi­ tion of [(TpPh,Me)ZnOH] in the presence of 2-mercaptoethanol (02IC5075, 02ICA459). A direct synthesis of metallocycle 46 was later obtained by the reaction of zinc perchlorate with 5-methyl-3-phenylpyrazole and NaOH in hot MeOH, followed by addition of 2-mercaptoethanol in 20% yield after recrystallization. An additional example containing diazole ligands was reported by Mak et al. (01AGE1725), whereby the sodium salt Na(Acntb) [where HAcntb = N-[N0 -(carboxymethyl)benzimidazol-2-yl-methyl]-N,N-bis (benzimidazol-2-ylmethyl)amine] was treated with an equal molar amount of Cu(ClO4)26H2O in ethanol to give [Cu6(Acntb)6](ClO4)6nH2O (47), as green crystals. In the crystal structure of 47 (Figure 6b), each Cu(II) ion is

Scheme 19

22

Monica Soler et al.

(a)

(b)

Figure 6 X-ray crystal structure of (a) macrocycle 46 (03CC1278) (reproduced by permission from Royal Society of Chemistry) and (b) macrocycle 47 (01AGE1725) (reproduced by permission from Wiley-VCH).

coordinated by the four nitrogen atoms of the ligand, and the branching acetate group functions as a monodentate bridge between adjacent [Cu(Acnbt)]þ units to generate the hexameric motif. Formation of multi­ directional hydrogen bonds between the metallamacrocycles generates the 3D network.

3. SIX-MEMBERED RING HETEROCYCLES 3.1 Pyridine Sun and Lees crafted (01OM2353) two hexagonal phenylacetylenic struc­ tures, 53 and 54, that each contained two pyridine units with the nitrogen atoms directed toward the periphery of the macroring, for the purpose of self-assembling with transition metals. The dinuclear 4,40 -di-tert-butyl-2,20 ­ bipyridine Re(I) tricarbonyl complexes with these ligands were formed and their photophysical properties studied. The stepwise procedure for 53 and 54 (Scheme 20) began by reacting 3,5-dibromopyridine and 2-methyl-3-butyn-2­ ol using Sonogashira—Hagihara cross-coupling conditions (75TL4467), fol­ lowed by deprotection to give 3,5-diethynylpyridine (49). Selective coupling with 1-bromo-3-iodobenzene gave the dibromobenzene analog 50, which was then coupled with trimethylsilylacetylene affording 51. Deprotection of the trimethylsilyl groups gave tetrayne 52 that was transformed to either the hexagonal macrocycle 53 using a Sonogashira—Hagihara cross-coupling or 54 via Hay coupling (62JOC3320, 93AGE406). During the same year, Tylwinski et al. reported (01OL1045) two other conjugated macrocycles, 56a and 56b, based on 2,6-diethynylpyridine

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

23

Scheme 20

subunits, again with the nitrogen atom of the pyridine subunits directed toward the periphery of the macroring. Synthesis of the ligands (Scheme 21) followed a Pd-catalyzed cross-coupling of dimethyl substi­ tuted vinyl triflate with 3,5-diethynylpyridine, followed by deprotection and oxidative homocoupling of the tetrayne using Hay conditions under high dilution. In the case of 56a (R = Me), the reaction afforded a mixture of the desired cyclic ligand as well as linear oligomers possessing limited solubility, which made purification difficult. To circumvent this problem, the combined mixture was treated with two equivalents of a Ru por­ phyrin complex, which rapidly coordinated the macrocycle, allowing purification by column chromatography, whose crystal structure is shown in Figure 7a. In the case of 56b (R = Ph), the macrocycle was isolated and coordinated with two Ru porphyrin units. Also, the reaction

24

Monica Soler et al.

Scheme 21 (a)

(b)

Figure 7 Crystal structure of (a) [Ru2(56a)] molecule (01OL1045) (reproduced by permission from American Chemical Society) (b) [Pt2(56b)2(PEt3)4](OTf)4 (02JA7266) (reproduced by permission from American Chemical Society).

of 56b with cis-(TfO)2Pt(PEt3)2 (02JA7266) afforded a different coordina­ tion arrangement, where each Pt ion was bound to two macrocyclic ligands and each macrocycle to two Pt atoms, forming the complex [Pt2L2(PEt3)4](OTf)4. The crystal structure is presented in Figure 7b. In 2004, the same group reported (04SL182) the successful synthesis of the fully conjugated macrocycle 57 based on 2,6-diethynylpyridine, where the lone pair of electrons of the pyridine units are directed inward, therefore featuring endotopic binding sites. The synthetic procedure to afford 57 basically followed the same strategy to that of 56, by a palla­ dium-catalyzed cross-coupling, followed by deprotection with NaOH and finished by a copper-catalyzed homocoupling reaction. Another example, macrocycle 58, was reported by Campbell et al. (03JOM379) containing two opposing pyridine units, whereby the two Pt atoms were incorporated in the macrocyclic framework. Construction started from oligomer 55b, which was desilylated using NaOH in THF-MeOH, and treated with [(PPh3)2PtCl2] under high dilution conditions in the presence of a catalytic amount of CuI at 50C for 14 h affording the bisPt macrocycle 58.

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

25

Stang et al. (09ACR249, 09JOC2) have made significant contributions to the self-assembly process. His eloquent use of transition metal hybri­ dization, predesigned, coordinating molecular architectures, and volumi­ nous work to categorize, define, synthesize, and bring to fruition utilitarian building blocks and supramolecular constructs have markedly influenced this burgeoning field. Toward these ends, Stang et al. has developed a wide range of eloquent architectures with esthetic and utilitarian appeal employing pyr­ idine—metal connectivity for self-assembly. In a report in 1997 (97JA4777), a bispyridinyl ketone (Scheme 22) and a 4,40 -bipyridine (donors) were employed as a corner unit and linear linker units, respectively, in the initial self-assembly of hexameric motifs with bisPt(II) (acceptor) com­ plexes 59 and 60. Notably, hexamer formation in quantitative yields using these building blocks was observed based on 1H and 31P NMR. Later, Stang et al. (07JA14187) employed these same bisPt(II) mono­ mers (59 and 60, Scheme 22) in conjunction with the 120 juxtaposed bipyridinyl crown ether monomer [61, prepared from connection of the crown ether to 3,5-bis(pyridine-4-ylethynyl)phenol. Treatment of the angular bisPt(II) bipyridinyl ketone smoothly afforded the desired tris (crown ether). Upon addition of the barbell-like bisbenzyl ammonium triflate salt 62 the supramolecular tris[2]pseudorotaxane hexamer 63 with a cavity diameter of 2.9 nm was formed. Transformation of the Stang’s alkyne-extended, bipyridine crown ether to the corresponding bipyridine benzyl ether dendron 64 [dendrons developed by Frechet et al. (90JA7638)] and assembly with the linear bisPt(II) monomer 65 gave the dendronized hexamer 66. Hexamers were prepared using building blocks possessing dendrons constructed through the third generation [G0—G3]. ESI and ESI-FT-ICR mass spectro­ metry facilitated characterization of these novel materials. Stang et al. (08JA839) have analogously designed and constructed ferrocene-modified hexamers. Reaction of ferrocene-1-carboxylic acid

26

Monica Soler et al.

Scheme 22

with 3,5-bis(pyridin-4-ylethynyl)phenol generated the bipyridine donorbuilding block that when treated with either the angular bisPt(II) ketone 60 or the linear bisPt(II) spacer unit 65 gave the tris(ferrocene) hexamer 67 (3.3 nm diameter) and the hexakis(ferrocene) hexamer 68 (5.3 nm dia­ meter), respectively. The metallocycles electrochemistry and mass spec­ troscopy were discussed.

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

27

Attachment of the crown ether moieties to the bisPt(II) diacetylene phenol acceptors to generate poly(crown ether) hexamers and poly[2] pseudorotaxanes has also been reported (08JA5320). As well, a “mix­ and-match” approach whereby the crown ether-based, bisPt(II) acceptors and ferrocene-based bipyridine donors or crown ether-based, bisPt(II) donors and ferrocene-based bipyridine acceptors were used to construct heterofunctional macromolecular hexagons was described (09JOC4828). Reviews on coordination-driven metallocycles and metallocages and the requisite geometry of the building blocks necessary to construct them are available (00CRV853, 08CC5896, 08T11495). Metal—carbonyl dipyridine ligands for use in the construction of self-assembled pentagons have also been reported (09IC5590). Other examples of metallomacrocycles containing metals coordinated to pyridine- or pyrimidine-based ligands exhibiting hexameric architecture are known. Winpenny et al. reported (91CC1453) the formation of the crystalline [Cu6(mhp)12Na](NO3) (69) from the reaction of hydrated cup­ ric nitrate with the potassium salt of 2-hydroxy-6-methylpyridine (Hmhp). The crystal structure revealed a metallomacrocycle possessing a sodium ion within the cavity, whose source was not identified. A similar structure (Figure 8a) was also reported by Thornton et al. (95POL459), in which [Co6(mhp)12Na](O2CCH3) (70) was synthesized by the reaction of the sodium derivative of Hmhp with anhydrous cobalt(II) acetate in MeOH; the structure of 70 shows that the six cobalt atoms form a planar hexagonal ring with a cavity, which accommodates the central sodium atom (Figure 8b).

28

Monica Soler et al.

(a)

(b)

Figure 8 X-ray crystal structure of (a) [Cu6(mhp)12Na](NO3) (69) (91CC1453) (reproduced by permission from Royal Society of Chemistry), (b) [Co6(mhp)12Na](O2CCH3) (70) (95POL459) (reproduced by permission from Elsevier).

A copper-based hexamer with a pyridine-type ligand was also reported by Vittal et al. (03IC5135). The macrocycle [Cu6(pgly)3(spgly)3]­ (ClO4)69H2O [71, Hspgly = N-(2-pyridylidene)glycine] was synthesized from an equimolar reaction of [Cu(pgly)2]2H2O [Hpgly = N-(2-pyridyl­ methyl)glycine] and Cu(ClO4)26H2O in MeOH giving dark blue hexago­ nal crystals. The crystal structure (Figure 9a) shows a hexameric macrocycle composed of two crystallographically independent Cu(II) atoms, a reduced Schiff base ligand (pgly) and a Schiff base ligand (spgly), arranged alternatively in the hexanuclear cation. Cui et al. (08JA4582) reported the metallomacrocycle [Zn6L6] (72) [H2L = (R,R)-()­ N,N0 -bis(3-tert-butyl-5-(4-pyridyl)salicylidene)-1,2-diaminocyclohexane], synthesized by the reaction of Zn(NO3)2 with the ligand H2L. The Schiff base ligand (Figure 9b, top) (01IC3222, 01TL2093) was obtained starting with the functionalized salicylaldehyde, which can be prepared by Suzuki coupling between the bromoaldehyde and 3-pyridinylboronic acid. Sub­ sequent condensation of the functionalized salicylaldehyde with 1,2-dia­ minocyclohexane in refluxing EtOH afforded 72. The crystal structure of the metallomacrocycle 72 (Figure 9b, bottom) showed that each Zn ion coordinates to the central N2O2 donor of the ligand and to a pyridine of another ligand building a hexameric metallocycle, with one uncoordinated pyridine. Noncovalent interactions between the macrocycles directed the packing of the different hexamers into a 3D nanotubular architecture.

3.1.1 Hexapyridine Newkome and Lee reported (83JA5956) the first successful synthesis of the quintessential, pyridine-based unsubstituted hexamer 77 termed

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

29

Figure 9 X-ray crystal structure of (a) [Cu6(pgly)3(spgly)3](ClO4)69H2O (71) (03IC5135) (reproduced by permission from American Chemical Society) and (b) [Zn6L6] (72) (08JA4582) (reproduced by permission from American Chemical Society), along with the corresponding ligand drawings.

“sexipyridine” (Scheme 23) starting from the oxidation of 6,60 -dimethyl­ 2,20 -bipyridine to the dialdehyde 73. The aldehyde groups were subse­ quently protected as thioacetals 74 using a catalytic amount of

Scheme 23

30

Monica Soler et al.

p-toluenesulfonic acid. Lithiation of the bis-dithiane 74, followed by addi­ tion of 1,3-dibromopropane (two equivalents) afforded the cyclic tetra­ dithiane 75. Deprotection using NBS allowed the isolation of the flexible tetraketone macrocycle 76, which was finally converted to the desired sexipyridine 77 by treatment with hydroxylamine in refluxing glacial acetic acid for 24 h. A notable attribute of sexipyridine is the nonplanarity of the connected pyridine rings due presumably to crowding of the adjacent lone N-electron pairs. Calculations suggest a gas-phase lowest energy D3 conformation with ‘up’ and ‘down’ alternating nitrogens (99JCS(P2)2501). Several derivatives of sexipyridine have since been reported. Toner reported (83TL2707) the synthetic procedure of an aryl derivative 78, which was formed using a tandom Kro¨hnke pyridine synthesis (63AG181, 76S1) as the key cyclization step (Scheme 24). The presence of Naþ in the mass spectrometry and elemental analysis was explained, after attempts to minimize metals during synthesis, with the possibility that the sexipyridine was capable of stripping Naþ from glass. Potvin et al. (03CJC209) described the synthesis of the trisubstituted cyclic hexamer 84 that exhibited unexpectedly poor solubility. Two syn­ thetic procedures were described (Scheme 25) to synthesize 84, coupling of a bis-propenone 80 with a diacetylterpyridine 81 in the presence of a source of NH3 via a dihydropyridine intermediate, or coupling of a more elaborate bispropenone 82 with the salt 83 under Kro¨hnke conditions. Heterokekulenes, the heteroatomic analogues of kekulene (78AGE372), are classic examples of hexameric molecules composed of fused, cyclized benzenoid rings. Dodecahydro-18,21-dioxoniakekulene (93), the first heterokekulene, was reported by Katritzky and Marson (83JA3279), contained two opposing oxygen atoms within the cavity’s

Scheme 24

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

31

Scheme 25

interior. Synthesis of the heterokekulene 94 containing two opposing nitrogen atoms was also presented (Scheme 26). Acylation of 9,10-dihy­ drophenanthrene at the 2-position with succinic anhydride gave 85, which was reduced using a Lock modification of the Wolff—Kishner reduction (48MI1) to afford the acid 86. Esterification with methanol to give the ester 87, which was acylated at the 7-position with
-(methox­ ycarbonyl)propionyl chloride to afford monoketone 88. Saponification of the keto diester, followed again by the Lock modification of the Wolff—Kishner reduction afforded the diacid 90. Anhydrous hydrogen fluoride was used under mild conditions for the cyclodehydration of the diacid to form the pentaphenedione 91, which following a Vilsmeier—Haack reaction (76MI1) afforded the required bis(b-chlorovinyl) dialdehyde 92. Condensation of the diketone 91 with the dialdehyde 92 afforded 93 in 87%. Under aldol conditions, the condensation of 91 with 92, followed by ring-closure afforded a highly insoluble mixture. Mass spectrum detected a peak assigned to the diazakekulene and others assigned to its successive dehydrogenation to afford the fully unsaturated azakekulene 94. The first hexaazakekulene was synthesized (Scheme 27) by Staab et al. (85TL6179), which contained six coplanar nitrogen atoms ideally juxta­ posed for the complexation of small ions. Catalytic hydrogenation of 95 gave 96, which was condensed with benzaldehyde to yield the 2,13­ dibenzylidene derivative 97 and ozonized at —78C to produce the

32

Monica Soler et al.

Scheme 26

Scheme 27

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

33

diketone 98. Reaction with POCl3 in DMF [Vilsmeier reaction (76MI1, 92T3659)] afforded b-chlorovinylaldehyde 99, which when treated with perchloric acid/acetic acids gave dodecahydro-19,20,22,23-tetraaza­ 21,24-dioxoniakekulene (100). Treatment with ammonia in MeCN under reflux conditions gave a yellow powder, assigned by 1H NMR to the D6h­ symmetrical dodecahydro-19,20,21,22,23,24-hexaazakekulene (101). In general, the reported heterokekulene rings have shown very low solubility thereby hindering their characterization and study. In an attempt to solve this problem, Bell and Firestone (86JA8109, 87JIP149) synthesized the toroidal dodecahydrohexaazakekulene (108) macrocycle, a C3-symmetric hexaazakekulene derivative with rigidifying ethylene bridges and three n-butyl groups to enhance its solubility (Scheme 28). The n-butyloctahydroacridine (102) was converted in three steps to ben­ zylideneketone 103 and then dimerized by pyrolysis of the trimethylhy­ drazonium salt, yielding dibenzylideneheptacycle 104. Ozonolytic cleavage of the benzylidene groups afforded diketone 105. The comple­ mentary segment, bis(b-dimethylaminoenone) 107, was prepared from

Scheme 28

34

Monica Soler et al.

102 via dibenzylidene derivative 106, which was ozonized. The resulting ketone was treated with Bredereck’s reagent (68CB41) to afford 107. Macrocyclization was performed by heating 105 and 107 with triflic acid in acetic acid, followed by addition of ammonium acetate, and lastly neutralization with LiOH. The presence of Ca2þ ion in the structure was determined to come from a 0.3% impurity of Ca2þ in the triflic acid. The torand 3,9,15,19,21,23-hexaazakekulene (112) with six nitrogen atoms that are alternately located at the inner and outer loci on the cycloarene (Scheme 29) has been reported (97AGE1190). Monoprotected proflavine 109 was reacted slowly with 0.5 equivalent of paraformalde­ hyde to give tripyridinyl diamine 110. Removal of ethoxycarbonyl under basic conditions afforded 111, which produced 112 upon stoi­ chiometric reaction with proflavine and two equivalents of paraformaldehyde. An analogous shape-persistent cyclic hexamer possessing six pyridine rings connected by triple bonds, the pyridinophane 122 (Scheme 30), has been reported by Tobe et al. (00OL3265). Employing a Sonogashira cou­ pling (75TL4467, 02JOM46, 08JOC6037), the n-octyl ester 113 was con­ verted to the bis(trimethylsilyl)ethynyl derivative 114, which was deprotected with K2CO3 affording 115 as well as completely deprotected and starting material. Two molecules of 115 were then coupled oxida­ tively giving 116. Deprotection of 116 again gave a mixture of partially 117 and completely deprotected 118, as well as starting material. Purified 118 was brominated with NBS giving 119 and then reacted with two equivalents of 117 to afford the linear hexamer 120. Deprotection gave the unstable linear hexamer 121, which was subjected to an intramolecu­ lar coupling to form the cyclic hexamer 122. Another example of a heterocyclic macromolecule containing six pyr­ idine subunits reported by Miyazaki et al. (02TL7945) was N,N0 ,N00 ,N000 , N0000 ,N00000 -hexamethylazacalix[6](2,6)pyridine 123 (Scheme 31), which exhibited more flexibility than previous examples and possessed the pyridine subunits directed towards the ring cavity, able to coordinate

Scheme 29

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

Scheme 30

35

36

Monica Soler et al.

Scheme 31

Zn(II) ion. The Pd-catalyzed aryl amination of 2,6-dibromopyridine with 2,6-bis(methylamino)pyridine afforded (10%) the hexameric heterocycle 123. The cyclization of reaction of 2-bromo-6-(methylamino)pyridine also gave the corresponding macrocycle in 8% yield.

3.1.2 Bipyridine Routes to hexameric architectures based on bipyridine have been the subject of design by many researchers, including Schlu¨ter, who continues to pioneer synthetic chemistry in numerous areas, including polymer, material science (09AGE1030), and macrocyclic chemistry (07EJO2700). Schlu¨ter et al. have prepared 2,20 -bipyridine-based macrocycles periph­ erally modified with six hexyloxy groups [as well as others (02EJO3075)] to enhance the ring’s solubility and obtained the X-ray structure (00CEJ2362) and also reported on the macrocycles ruthenium complexa­ tion and X-ray structure determination (02CEJ357). Illustrative of key transformations employed for the construction of these novel materials is the synthesis of macrocycle 127 (Scheme 32) (05EJO822). Beginning with 5,50 -dibromobipyridine, a Suzuki cross-coupling with a hexyloxy­ benzyl arylborate afforded the elongated bipyridine 124 that was then transformed (ICl) to the diiodobipyridine and connected to two equiva­ lents of iodophenylacetylene via another cross-coupling reaction to give the extended diiodide 126. Strategic use of THP protecting groups allowed the incorporation of polymerizable pendant groups, such as methyl methacrylate and norbornene, thereby facilitating their use as macromonomers in free radical and ring-opening metathesis polymeriza­ tions. A final coupling with the intermediate bisacetylene 125 gave the hexamer 127. Oxidative treatment [Cu(OAc)2 or CuCl/CuCl2] of the diiodide 125 generated a series of polydiacetylenes 128 (08OL2091). The coordination of osmium and ruthenium as their trisbipyridine complexes (Scheme 33) has been reported (06CPC229). Treatment of the macrocycle 127 with Os(bipy)2Cl2 gave the monometallated specie 129

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

37

Scheme 32

that was then reacted with a second equivalent of the metal adduct Ru(bipy)2Cl2 to afford the bismetallated macrocycle 130. Photoinduced energy and electron-transfer processes of the Ru(II)—Os(II), Ru(III)—Os(II), and Ru(II)—Os(III) complexes were examined; the macrocyclic ligand was reported to be a “relatively poor conducting bridge.” Schlu¨ter et al. (07EJO2700) have also reported the preparation of shape­ persistent, 6-sided macrocycles that incorporated site-specific functionaliza­ tion along with the opposing 2,20 -bipyridine units. Coumarin 2 and 343 dyes

38

Monica Soler et al.

Scheme 33

were attached to the corners as energy-absorbing groups in anticipation of the use of these materials as energy- and electron-transfer devices (131—133). Protonation of the coumarin moieties caused significant changes in the

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

39

Scheme 34

absorption and emission properties due to excited-state order inversion and electron-transfer quenching mechanisms (08CEJ10772). The research group of Jean-Marie Lehn, who pioneered supramo­ lecular chemistry, (95MI1) has reported the construction of hexanuc­ lear architectures termed helicates (97JA10956) based on the self-assembly of tris-2,20 -bipyridine ligands with Fe(II) (Scheme 34). Preparation of the ethylene-bridged ligand 134 (93AGE703) was accomplished by mono-lithiation of 4,40 -dimethyl-2,20 -bipyridine and reaction with 4,40 -dibromomethyl-2,20 -bipyridine. Treatment of these ligands with Ni(II) gave the self-assembled trinuclear helix; whereas, reaction with FeSO4 in ethylene glycol (170C) afforded the hexame­ ric helicate 135 as a red precipitate in quantitative yield. Similar oligobipyridines employing bismethylene(oxy) connectivity have

40

Monica Soler et al.

Scheme 35

been reported (91HCA594) and demonstrated to form tetranuclear helicates (97JA10956). Hexameric helicate 136 was reported by von Zelewsky et al. (98AGE289) using chiral bis(pinene-2,20 -bipyridine) ligands for the coor­ dination of six Ag(I) ions; an X-ray structure was also reported (Scheme 35; X-ray crystal structure of 136 (98AGE289), reproduced by permission from Wiley-VCH). Potts et al. (93IC4436, 93IC4450) described the construction of helical, dimeric species by the reaction of an oligo­ meric septapyridine with Cu(II) and Co(II). Kelly et al. (97JOC2774) have prepared cyclo-2,20 :40 ,400 :200 ,2000 :4000 ,40000 :­ 0000 00000 00000 2 ,2 :4 ,4-sexipyridine consisting of cyclic-bound bipyridine with the nitrogen lone pair electrons directed outward from the periphery of the hexamer. This is in contrast to the sexipyridine constructs prepared by Newkome et al. (83JA5956) and Toner (83TL2707) whereby the nitrogens are directed toward the center of the hexamer. The tris-bipyridine hexamer 142 synthesis began (Scheme 36) with 2,20 -dibromo-4,40 -bipyridine [prepared by subjecting 4,40 -bipyridine to the Chichibabin reaction (42MI1) to give the diamine, followed by diazotization (HNO2, Hþ), hydrolysis, and bromination (POBr3)]. The dibromide 137 was subjected to halogen-metal exchange/Stille coupling (06EJO1827) to give the quaterpyridine 138 that was subsequently reacted via another Stille coupling with (trimethyltin)pyridine 139 to generate the quinquepyridine 140. The sixth and final pyridine ring was constructed by transformation of the arylbromide to a masked acetyl group by Stille coupling with ethylvinyl ether and treatment with NBS to give the bromoacetyl moiety. Addition of pyridine gave the pyridinium bromide 141 that under acidic conditions with added

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

41

Scheme 36

NH4OAc underwent a Kro¨hnke reaction (76S1) to afford the desired hexameric trisbipyridine 142. The authors noted that in some cases the Pd(PPh3)4-promoted Stille couplings were sensitive to the use of freshly prepared catalyst. As well, Sonogashira coupling of alkyne moieties to 5,50 -dibromo-2,20 -bipyridine in anticipation of generating bipyridine-based hexamers with alkyne spacers was unsuccessful.

3.1.3 Terpyridine Schlu¨ter et al. (00EJO3483) have prepared terpyridine-based macrocycles where the polypyridine units are incorporated linearly in the framework. This is analogous to that of their bipyridine-based hexam­ ers (05EJO822, 06CPC229, 08CEJ10772). Construction started with the Pd-catalyzed cross-coupling of the bis(trialkyltin)pyridine 143 (Scheme 37) with a bromopyridine to give the bisboronated terpyridine 144. Cou­ pling to the corresponding diiodide 145 generated the macrocycle 146. Notably, this was the first synthesis of an expanded sexipyridine. Expanded phenylacetylene-modified terpyridine-based macrocycles have been reported (03JA6907) along with the X-ray crystal structure of an alkyl-substituted ring.

42

Monica Soler et al.

Scheme 37

Newkome et al. (99AGE3717) first reported in 1999 the synthesis of hexaruthenium macrocycles based on the self- and directed-assembly of bis(terpyridinyl) monomers [based on the 2,20 :60 ,200 -terpyridine moi­ ety initially reported by Morgan and Burstall (32JCS20, 37JCS1649)] crafted with a 120 angle between the two coordination sites. This facilitated the positioning of six bisterpyridine ligands in the ubiqui­ tous benzenoid motif. Construction of these metallohexamers (Scheme 38) began with the treatment of aryldialdehyde 147 with excess 2-acetylpyridine and base, followed by NH4OAc and HOAc to give (66%) the requisite bis(terpyridine) 148. Reaction of 148 with RuCl3nH2O afforded the corresponding paramagnetic bisRu(III)

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

43

Scheme 38

adduct 149 that was subsequently reacted with 148 under reducing conditions (N-ethylmorpholine) in a 1:1 ratio to give the hexaRu(II) metallocycle 150 in ~40% yield after purification. As a proof-of-struc­ ture, the identical macrocycle was synthesized by a directed, step-by­ step approach that was achieved starting by reacting the bisRu(III) adduct 149 with two equivalents of the ligand 148 to give the bisRu(II) trimer 151. Upon further conversion to its bisRu(III) adduct (1512Ru (III), not shown) and reaction with the unmetallated trimer 151 (essen­ tially a top-half : bottom-half coupling strategy) the hexamer 150 was obtained. Ultracentrifugation absorption profiles for this macrocycle yielded an average molecular weight for the macrocycle of M = 5600 + 200 amu, which corresponded well with the calculated value (M 5670 amu with counter ions). A bromodialdehyde was also employed to construct a bromoaryl bisterpyridine ligand that gave rise to an alternating methylaryl—bromoaryl substitution pattern on the macro­ cyclic ring (150). These Ru-based metallomacrocycles have been

44

Monica Soler et al.

examined by electrospray ionization (ESI) and matrix-assisted laser desorption ionization (MALDI) mass spectrometry (06IJMS86). Opti­ mal parameters for mass analysis were developed. Traveling wave ion mobility mass spectrometry (TWIM-MS) has been employed for the analysis of similar Cd(II)-based hexamers (09JA16395). It was found that ion mobility separation enhances the resolving power of the mass spectrum by the addition of shape-dependent dispersion thereby facilitating the identification of different conformations in supramole­ cular assemblies. Transmission electron microscopy of the Fe(II) metallohexamer with hydroxymethyl substituents (150c) clearly revealed a hexameric structure that corresponded well with ˚ , respectively, the outer and inner dimensions of 37.5 and 17.5 A obtained by molecular modeling (02CEJ2946). Incorporation of different metal centers (Scheme 39) within the hexameric framework was also examined (04CEJ1493). Self-assembly of the bisRu(II) trimer 151 with one equivalent of FeCl2 afforded the tetraRu(II)bisFe(II) architecture 153 (—4—2—); whereas, when the

Scheme 39

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

45

monoRu(II)bisterpyridine dimer 152 was treated similarly (1 equiv. FeCl2) the trisRu(II)trisFe(II) motif 154 (—3—3—) was obtained. A pentakisRu(II)monoFe(II) metallocycle (not shown) was also prepared starting with the monoRu(II)bisterpyridine dimer 152, the successive addition of two equivalents of RuCl3 followed by two equivalents of bisterpyridine ligand, and finally closing the ring with one equivalent of FeCl2. An electrochemical analysis of the Ru-Fe-based structures was reported and compared with that of all the Ru(II) and Fe(II) hexamers; the reversible redox characteristics of this family of metallomacrocycles suggested their suitability for further study as candidates for electron storage devices. Notably, a series of oligomeric < tolyl ½bisðterpyridinyl Þ  n RuIIn1 > complexes, where n= 2—6, possessing metal-free terpyridine end groups, was formed and isolated in a single-pot reaction (06EJO4193); UV-Vis, CV, MS, and NMR data for the oligomers are compared and contrasted to that of the corresponding hexamer 150 (Scheme 38) that was also isolated from the reaction. Other unique bis(terpyridine)-building blocks have been reported, such as the 5-substituted 1,3-[bis(2,20 :60 ,200 -terpyridin-40 -ylethynyl)]ben­ zenes (06DMP413). A Pd-catalyzed cross-coupling procedure was employed to build these elongated, functionalized bis(terpyridine) ligands that were readily self-assembled to afford the corresponding hexameric metallomacrocycles possessing an inner void diameter of ˚ . Starting with the appropriate 1,3-dibromobenzene (Scheme 40), 24 A TMS-acetylene was coupled [Pd(dba)2, CuI, Et3N] to give the diacetylene 155 that was subsequently coupled to terpyridine triflate 156 (91JOC4815) via a Pd(0) cross-coupling procedure to afford the desired elongated bisterpyridine monomer 157. Treatment of the building block 157a with FeCl2, followed by ion exchange with NH4PF6, gave the expanded hexamer 158. A terpyridine-based, Zn(II)-hexamer has been reported (06MMRC1809), whereby an O-hexyl-3,5-bis(terpyridine)phenol ligand was prepared (04OL1197) and subsequently self-assembled. The photoand electroluminescence properties of the hexamer were investigated in solution and coated onto ITO glass. The HOMO and LUMO energy gap of the Zn-hexamer was determined to be 3.5 eV. Fabrication into an OLED device resulted in green electroluminescent emission at 515 nm with a maximum luminance of 39 cd/m2 and maximum efficiency of 0.16 cd/A. A novel use of Newkome’s hexameric metallomacrocycles has been their incorporation into dendrimer—hexamer composite materials (08AM1381). Composite fiber formation was effected by the ion-pro­ moted, stoichiometric self-assembly of a structurally rigid hexameric macrocycle and a dodecacarboxylate-terminated, first-generation dendri­ mer (94MM3464) where the metallocycle and dendrimer function as

46

Monica Soler et al.

Scheme 40

polyionic counter ions. The hexamers were prepared (40—45%) by react­ ing O-hexyl-3,5-bis(terpyridinyl)phenol (04OL1197) with one equivalent of [Ru(Cl)2(DMSO)4] (88IC4099). The anionic G1 dendrimer (prepared by hydrolysis of the corresponding 12-tert-butyl ester with formic acid) ˚ at basic pH, as determined possesses a hydrodynamic diameter of 23.6 A by 2D diffusion-ordered spectroscopy NMR experiments. Notably, this ˚ ) of the diameter is larger than the internal void region diameter (17.5 A hexamer that suggests an ordered molecular packing based on a symme­ trical association of the dendrimer smoothly fitting above, and not entirely into, the cavity of the hexamer. Fibers were formed by carefully layering a solution of polycarboxylate dendrimer in MeOH and water on top of a deep red MeCN solution of hexamer and allowing the mixture to

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

47

set at 25C for 2 weeks in a sealed vial. The fibers were isolated by filtration and characterized by selected area electron diffraction, which indicated columnar packing of alternating hexamer and dendrimer spe­ cies with 1.92 nm between hexameric planes and 3.85 nm between the centers of adjacent columns. Fiber formation has also been observed (10CEJ1768) based on the packing of sugar-modified hexamers and the corresponding pentamer upon slow diffusion in a mixed solvent (CHCl3/ MeOH/MeCN; 8:3:1). Fiber diameters ranged from 10 to 80 nm and possessed a helical morphology. The photophysical properties of similar metallocycles possessing per­ ipheral tert-butyl groups have been reported (07ICA1780), whereby the incorporation of alkyne moieties in the framework was studied. It was determined that the ethynyl groups could facilitate electron trapping and enhance molar extinction coefficiency and photocurrent generation. Newkome et al. (06JCD3518) have also prepared metallomacrocycles using triphenylamine as the design element that instills the 120 (or nearly so) required for benzenoid architecture. The terpyridinyl building block was constructed (Scheme 41) by subjecting commercially available triphenylamine to a Vilsmeier—Haak reaction (POCl3, DMF) to generate dialdehyde 159. Treatment of the dialdehyde with 2-acetylpyridine and base followed by NH4OH and HOAc afforded the desired 4,40 -bis (2,20 :60 ,200 -terpyridinyl)triphenylamine 160. The X-ray crystal structure of this monomer revealed a nearly planar triarylamine group with the terpyridine ligands oriented 119.69 with respect to their coordination sites. Reaction of the bisligand 160 with FeCl2 or Zn(BF4)2, followed by ion exchange (NH4PF6), gave the hexaFe(II) 161a and hexaZn(II) 161b macrocycles, respectively. UV-vis absorption and emission spectra for the metallocycles revealed that both metallomer emissions occurred at max ffi 575 nm with metal-to-ligand charge transfer at max ffi 582 nm suggest­ ing these materials as useful sensitizer components in dye-sensitized solar cells. The design and synthesis (Scheme 42) of the first non-branched fractal polymer that is the molecular equivalent of a “Sierpinski hexagonal gasket” has been described by Newkome et al. (06SCI1782). Fractal con­ structs are based on the incorporation of identical motifs that repeat at differing size scales. Thus, this polymer was created based on repeating hexameric architectures incorporated with increasing dimensions at suc­ cessive higher levels or generations. Based on the Polish mathematician Vaclov Sierpinski’s 1915 fractal definition (15CR302) and the collection of equilateral triangles termed the “Sierpinski gasket” by noted mathemati­ cian Mandelbrot (82MI1) this non-dendritic, fractal polymer possesses 24 bisterpyridine and 12 tristerpyridine building blocks (a total of 84 terpyr­ idine moieties) bound together with 42 divalent Ru (36) and Fe (6) metal centers. Preparation began by treatment of 1 equiv. of bis[Ru(III)]

48

Monica Soler et al.

Scheme 41

monomer 149 with 4.5 equiv. of tristerpyridine 162 [prepared according to the procedure of Constable et al. (92CC617)] (CHCl3/MeOH, cat. N­ ethylmorpholine) to give (35%) the heterotrimer 163. Coupling of 163 with homotrimer Ru(III) adduct 164 in the presence of N-ethylmorpho­ line generated (31%) the hexamer 165 possessing the 120 juxtaposed free ligands required for the next stage of hexamer formation; reaction of the building block 165 with FeCl2 afforded the gasket 166 that was isolated as the polyCl salt that exhibited good solubility in MeOH, EtOH, DMF, and DMSO and poor solubility in H2O, CH2Cl2, and MeCN; counter ion exchange to the polyPF 6 salt changed this trend to facilitate solubility in MeCN, DMF, and DMSO and insolubility in MeOH, EtOH, and CH2Cl2. Characterization of this novel hexamer included TEM, AFM, and ultrahigh-vacuum low-temperature (8 K) STM, which combined

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

49

Scheme 42

with traditional techniques (e.g., NMR, UV-vis) provided a “visual” argument for the formation of the 12-nm diameter hexamer. A series of shape-persistent hexagonal macrocycles based on trimeric bisterpyridine-Fe(II) connectivity (Scheme 43) has been reported (08EJO3328). Differing spacer groups were employed for coordination site

50

Monica Soler et al.

Scheme 43

separation in the bisterpyridine building blocks. Construction of the building blocks was effected by coupling terpyridine precursors either with them­ selves or with the appropriate spacer moiety. Thus, bisterpyridine 167 was prepared by treatment of 40 -(3-bromophenyl)-2,20 :60 ,200 terpyridine [obtained

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

51

by the reaction of the commercially available 3-bromobenzaldehyde with 2-acetylpyridine under basic conditions, followed by the addition of excess NH4OAc in HOAc (07JCD626)] with bis(pinacolato)diboron employing a [Pd(dppf)2Cl2]-catalyzed coupling (95CR2457). Similar Pd-promoted cou­ plings using the corresponding ethynyl-substituted terpyridine, boron pin­ colate esters, and aryl alkynes generated the elongated bisterpyridine monomers 168—170. Reaction of each monomer with FeCl2, followed by NH4PF6 counter ion exchange, gave the desired family of hexamers 171—174. Solubility of the series generally increased as spacer length increased; however, the bisterpyridine obtained by coupling of the ethynylsubstituted terpyridine with 1,4-diiodobenzene (i.e. the alkyne-modified homolog of 169) exhibited poor solubility thereby prompting the synthesis of the alkoxy-modified terpyridine 169 for use in metallocycle construction. Newkome et al. (05AGE1679) have described a reversible, assembly— disassembly procedure using a hexametallomacrocycle containing twelve terpyridine groups enclosed within a 114-membered macrocyclic struc­ ture (Scheme 44). Self-assembly of a bisalkene-modified bisterpyridine monomer 175 with FeCl2 gave the Fe-based hexamer with peripheral

Scheme 44

52

Monica Soler et al.

alkene groups 176 that were readily connected by use of the Grubb’s catalyst to give an imbedded metallocycle 177. Treatment with base (K2CO3, DMF) quantitatively displaced the metal centers to afford a cyclic array of bound bisterpyridine ligands 178. In the presence of more FeCl2, the hexameric motif was readily regenerated. Proof-of-structure included reduction of the alkene moieties and also Pd-mediated hydrogenation of the benzyl ether groups to recover the starting bisterpyridine ligands. Eryazici and Newkome (09NJC345) have reported the synthesis of substituted bisterpyridine-building blocks based on a two-step Kro¨hnke (76S1) procedure. This has allowed the construction of Fe(II)—Ru(II) hexamers (Scheme 45) with terpyridine-based substitution. For

Scheme 45

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

53

example, treatment of bromoterpyridine 179 with an iodomonoterpyr­ idineRu(III) adduct gave the diiodobisRu(II) complex 180. Pd-promoted coupling of the alkyne-modified terpyridine 181 generated the free ligand intermediate 182 that when treated with FeCl2 gave the desired macrocycle 183.

3.2 Pyrimidine A hexameric macrocycle containing two pyrimidine units has been reported by Kauffmann et al. (75AGE714), where the lone pairs of the pyrimidine ligands are directed toward the periphery of the macrocycle. The macrocycle is aromatic and was synthesized in a two-step reaction (Scheme 46), where 4-(3-bromophenyl)pyrimidine was reacted with (3-bromophenyl) lithium forming 184, followed by a homocoupling in the presence of CuCl2 to afford 185. Examples of cyclic hexamers containing pyrimidine-type ligands have been found in the literature (05JSSC2436), such as with 2-pymoH (2-hydro­ xypyrimidine) or 2-dmpymoH (4,6-dimethyl-2-hydroxypyridine). Reaction of metals such as Ag and Cu with these ligands formed a combination of macrocycles and 1D polymers. Sironi et al. (97IC5648) showed that addition of Et3N to a water MeCN solution of AgNO3 and 2-pymoH afforded the cyclic hexamer [Ag(2-pymo)]6. If the same reaction is conducted in water, [Ag(2-pymo)]n is formed, which can be converted to the more thermody­ namically stable cyclic hexamer by heating above 150C or by suspension at room temperature in anhydrous HC(OEt)3 for 12 h. A similar example was also reported (98AGE3366) where [Cu(MeCN)4](BF4) and NEt3 were reacted to form a microcrystalline precipitate, composed of cyclic hexamers and helical polymers as revealed by crystal structure determination, sug­ gesting a low energy barrier between the two products. Finally, an example of an enantiomeric pure hexamer was reported by Lippert et al. (03CEJ4414) [(R,R-/S,S-dach)Pd(2-dmpymo)6]6(NO3)6 (186) (dach = 1,2-diaminohex­ ane). The self-assembly reaction of cis-[(dach)Pd(H2O)2]2þ and 2-Hdmpy­ moH in an aqueous solution, followed by concentration of the reaction

Scheme 46

54

Monica Soler et al.

Figure 10 X-ray crystal structure of 186 (03CEJ4414) (reproduced by permission from Wiley-VCH).

medium by 1/3 afforded, after 7 days, crystals of the cyclic tetramer [(R,R-/ S,S-dach)Pd(2-dmpymo)6]4(NO3)6. Following the same synthetic proce­ dure, but without concentration, crystals of the cyclic hexamer 186 were isolated after 4 days. The crystal structure (Figure 10) revealed that the Pd binding occurs at the N1 and N3 donor atoms of the pyrimidine ring, where the six Pd centers lie on a plane, and the pyrimidine rings are not coplanar with the Pd6 plane but exhibit a 1,3,5-alternating arrangement.

3.3 Phenanthroline Loeb et al. (98AGE121) employed commercially available 4,7-phenan­ throline, as a bridging ligand, for the construction of a 6-sided, hexaPd macrocycle (Scheme 47). Two hexameric complexes (187a and 187b) were prepared using the bispalladium adducts of either 1,2,4,5-tetrakis(n­ butylthiomethyl)benzene or 1,2,4,5-tetrakis(phenylthiomethyl)benzene for self-assembly with the phenanthroline ligand. The BF 4 salts of these materials were isolated as stable, yellow, microcrystalline solids, whose solubility was dependent on the R groups bound to the sulfur centers. The X-ray structure of the n-butyl derivative revealed a hexame­ ˚ in diameter. ric structure with a cavity of ca. 12 A

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

55

Scheme 47

Scheme 48

Lehn et al. (00CEJ4140) also described the self-assembly of rigid bis(bipyridine) ligands to form hexameric metallocyclophanes (Scheme 48). The key ligand 3,8-bis(2-pyridyl)-4,7-phenanthroline 188 was accessed by N-methylation of phenanthroline (MeI), Fe-promoted oxidation [aqueous

56

Monica Soler et al.

K2Fe(CN)6, base], concomitant demethylation and bromination (POBr3), and finally Pd(PPh3)4 mediated coupling of trimethyltinpyridine. Addition of Cu (II) ions to an MeCN solution of the ditopic ligand 188 gave the hexameric cyclophane 190 that exists in equilibrium with the tetrameric species 189. Formation of the tetrameric and hexameric species was observed to occur in the [Cu(II)] concentration range of 3.2  104 — 3.2  105 mol dm3 as evidenced by electrospray mass spectrometry (ES—MS). Notably, the tetramer was favored by lower metal ion concentration and the hexamer favored by higher concentration. MacDonnell and Ali have described (00JA11527) the construction of mixed-metal hexamers with diameters of 5.5 nm using the elongated bipyridine-based, building block tetrapyrido[3,2-a:20 ,30 -c:300 ,200 -h:2000 ,3000 -j] phenazine (tpphz). The stereochemistry of the -[(bpy)Ru(tpphz)2]2þ and D-[(bpy)Os(tpphz)2]2þ precursors directed macrocycle ring formation and facilitated the topospecific incorporation of different metals within the hexagon (Scheme 49). Thus, reaction of enantiomeric monomers 191 and 192 with (MeCN)4PdII afforded the cyclic hexagonal architecture 193 comprised of alternating Ru(II) and Os(II) metal vertices. A requirement of the planar self-organization of these building blocks is the alternating incorporation of the opposite chirality, as verified and supported by molecular modeling and temperature dependent 1H NMR studies.

3.4 Oligosaccharides Cyclodextrins, cyclic oligosaccharides made of a-(1!4)-linked D-gluco­ pyranose units, are of interest for synthetic chemists from a number of perspectives, including their chemical stability, potential for regioselec­ tive modification, and readily availability (94AGE803). Cyclodextrins were first isolated in 1891 by Villiers as degradation products from starch (91CR536), where the cyclodextrin glycosyl transferases (CGTases) enzyme essentially could detach a section of the starch helix and close the two ends of the fragment to form a cyclic molecule (80AGE344). However, CGTases are generally, nonspecific with respect to the fragment ring size, therefore the enzymatic degradation of starch affords a mixture of cyclic and linear maltooligosaccharides. Isolation of a particular cyclo­ dextrin was performed by the addition of selective precipitation agents, which in the case of the hexameric -cyclodextrin (194,  referring to 6 glucose units), included the addition of 1-decanol to afford the macrocycle in 40% yield (94AGE803). Modified synthesis of these ring struc­ tures have also been reported (87CAR277) where -cyclodextrin (194) could also be obtained in 0.3% overall yield in 21 steps starting from maltose. Cyclodextrins have been chemically modified in order to change their solubility or in the early literature for purification purposes, as well as for specific applications (80AGE344). Several examples of completely

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

57

Scheme 49

substituted -cyclodextrins have been reported (83T1417), these include acylated, alkylated, nitrated, silated, boronated, and aminated. Scheme 50 shows the direct acetylation of 194 to afford 195 (49JA353). Also of interest is the novel cyclic hexa-b-peptide 196 composed of acety­ lated glycosamino acid (GA). In solution, conformational changes from C3 to C6 symmetric structure upon elevation of temperature have been reported (07BPY150). The cyclic hexamer formed rod-shaped crystals with a C6 symmetric conformation that when examined using electron diffraction analysis demonstrating that the macrocycles stack to form nanotubes.

58

Monica Soler et al.

Scheme 50

4. MISCELLANEOUS HETEROCYCLIC MATERIALS 4.1 Flexible rings Interest in the structural topologies of metal-organic hybrids as well as in their potential properties led Lee et al. (09CENC43) to construct the flower-shaped cyclic hexameric structure of [Ag6(197)6(PF6)](PF6)5 (198), by the reaction of AgPF6 with the exodentate dithiamacrocycle ligand (197) (87JA4328, 92IC203, 00JCA652). Coupling of N-Boc-protected dithiol (00JCS(P1)3444) with 1,2-di(bromomethyl)benzene, followed by depro­ tection of the amine from the macrocycle (Scheme 51a; X-ray crystal structure of 198 (2009CEN43), reproduced by permission from Royal Society of Chemistry) generated the ligand 197. The crystal structure (Scheme 51b) revealed a flower-shaped cyclic hexamer, formed possibly due to the flexibility of the ligand as well as the stabilization provided by the anion.

59

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

a)

CH3

Boc

Boc2O

N H

Cl

N

Cl

SCOCH2

N SH

SCOCH3

1) base

Boc

Na, MeOH

Boc

KSCOCH3

N

AgPF6

SH

198 Br

Br

S

H N

S

2) TFA 197

b) S1 Ag1 S1A

S2 N1 P F

Scheme 51

4.2 Terpyridine and phenanthroline The heteroditopic ligand 201 composed of terpyridine and phenan­ throline subunits has been reported by Coronado et al. (08IC5197). The synthesis of 201 (Scheme 52; X-ray crystal structure of 202 (2008IC5197), reproduced by permission from American Chemical Society) relied on the pivotal cross-coupling of 5-(neophenyl glycola­ toboron)-5’’-methyl-2,2’:6’,2’’-terpyridine (199) to 3-bromo-8-(p-anisyl)­ 1,10-phenanthroline (200) with Pd(PPh3)4 in the presence of K2CO3 to afford the unique bisligand 201. Self-assembly with Cu(OAc)2 in MeOH, after recrystallization from MeCN, gave [Cu6(201)6(PF6)6] (PF6)6 (202) as green crystals. The X-ray crystal structure (Figure 11) revealed the cation [Cu6(201)6(PF6)6]6þ, where each Cu is coordinated to both a terpyridine and a phenanthroline unit of a different ligand with weakly bound PF6 ions completing the octahedral coordination spheres.

60

Monica Soler et al.

Scheme 52

4.3 Five- and six-membered In 1999, Tuchagues et al. (99IC1165) reported the synthesis and crystal structure (Scheme 53) of the self-assembled macrocycle [Cu6(L)6]6þ (204) (where L = N-(2-phenylimidazol-4-ylmethylidene)-2-aminoethylpyridine). The critical tridentate ligand, which was not isolated, was prepared by the addition of 2-aminoethylpyridine to 2-phenyl-4-formylimidazole in MeOH; the mixture was then heated for 1h. After preparation of the mononuclear Cu(II) complex 203, by reaction with CuCl22H2O, addi­ tion of triethylamine to a H2O—MeOH solution of 203 generated further

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

61

Figure 11 X-ray crystal structure of 211 (07AGE4073) (reproduced by permission from Wiley-VCH).

Cuii

Cuiii

Cui Cuiv N1i Cu N4

N1 Cuv

N3

Scheme 53

62

Monica Soler et al.

coordination involving the uncomplexed imidazolate nitrogens, to yield the cyclic construct 204. The crystal structure revealed that each Cu(II) ion was coordinated by three N-donor of the tridentate ligand and an adjacent imidazolate nitrogen. This is a good example of the inherent stability of the hexameric architecture. Nogami et al. reported (01IC3954) the discrete hexanuclear complex [CuX2(4PMNN)]6 (206) (X = Br, Cl) containing six Cu(II) ions and six 4-pyrimidinyl nitronyl nitroxide (4PMNN, 205) units. Synthesis of the bridging ligand 205 was achieved starting with 4-pyrimidinecarboxalde­ hyde, which was converted to the nitronyl nitroxide group by Ullman’s method of treatment with 2,3-bis(hydroxylamino)-2,3-dimethylbutane (72JA7049) (Scheme 54a; X-ray crystal structure of 206 (2001IC3954), reproduced by permission from American Chemical Society). A mixture of 205 with CuBr2 at room temperature gave, after a week, dark green crystals of the hexamer 206 where each pyrimidine bridges two copper ions, shaping a nanoscale cavity (Scheme 54b). Molecular arrangement in the crystal along the c-axis resembled a honeycomb-like channel structure. Cohen et al. reported (04AGE2385, 05IC4139) two different macrocycles [Cu(4-pyrdpm)(hfacac)]6 (209) and [Cu(4-quidpm)(hfacac)]6 (210) [where 4-pyrdpm = 5-(4-pyridyl)dipyrromethene and 4-quidpm 5-(4-quinolyl)dipyrromethene] composed of copper with dipyrro­ methene (dipyrrin) ligands. The reaction of the oxidized ligand with Cu (hfacac)2 afforded 209 and 210. Ligand synthesis (Scheme 55a; X-ray a)

b)

206

Scheme 54

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

63

b)

209

210

Scheme 55

crystal structure of 209 (2004AGE2385), reproduced by permission from Wiley-VCH) started with the condensation of 4-pyridinecarboxaldehyde or 4-quinolinecarboxaldehyde with pyrrole, followed by oxidation with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) to give the heterodi­ totic ligands 4-pyrdpm 207 and 4-quidpm 208, respectively. Addition of 1 equivalent of Cu(hfacac)2H2O (hfacac = hexafluoroacetononate) to the oxidized ligand in situ produced the heteroleptic complexes [Cu(4-pyrdm)(hfacac)] and [Cu(4-quindpm)(hfacac)], which were iso­ lated by flash chromatography in modest yield. Crystallization of these complexes revealed surprising structures; each complex self-assembled in two distinct supramolecular motifs: a discrete hexameric ring (209 and 210, Scheme 55b; X-ray crystal structure of 210 (2005IC4139), reproduced by permission from American Chemical Society) and a double-helical coordination polymer in the same crystalline lattice. Comparing both, the former has Cu(II) centers in the six-membered rings that are essen­ tially coplanar; while the latter, possesses Cu(II) ions exhibit a cyclohex­ ane-like “chair” conformation. Halcrow et al. reported (07AGE4073) the synthesis of a fluoro hexameric metallocrown by the reaction of CuF2 with one equivalent of

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3{5}-(pyridin-2-yl)-5-(tert-butyl)pyrazole (HL) (03JA10800) and nBu4NOH in MeOH. Evaporation of the solvent and recrystallization afforded [{Cu (-F)(HL)}6(H2O)2]8CH2Cl2 (211). Analogous reactions using NaOH or KOH afforded the crystal of 211, where the crystal structure (Figure 11) shows the same structure as 204, but with two water molecules com­ plexed by six F donors. Ammonium, alkylammonium and amino acid complexes have also been reported (08CEJ223).

4.4 Nucleobases, nucleosides, and nucleotides Some cyclic polynuclear metal complexes that include nucleobases have been synthesized, based on self-assembly. Labib et al. reported (88AGE1160) the hexanuclear metallomacrocycle incorporating six d8 platinum centers and six anions of the pharmacologically active pur­ ine base theophylline (Hthp). Reaction of [Me3Pt(H2O)3]2(SO4) and the potassium salt of theophylline in hot water afforded after recrystalli­ zation [Me3Pt(thp)]612CHCl3 (212) in 50% yield. The crystal structure (Figure 12a) revealed an hexameric heterocycle with S6 symmetry, where the Me3Pt moieties are coordinated in a cis-fashion by N7 and N9 or neighboring purine ligands. A hexanuclear platinum complex cis-[(PMe3)2Pt(9-MeGu (-H))]6(NO3)6 (213) formed with the nucleobase 9-methylguanine [9-MeGu(-H)] was reported by Valle et al. (95IC1745). Synthesis was started by the reaction of the ligand with cis-[(PMe3)2Pt(-OH)]2(NO3)2

Figure 12 (a) X-ray crystal structure of 212 (88AGE1160) (reproduced by permission from Wiley-VCH) and (b) X-ray crystal structure of 213 (95IC1745) (reproduced by permission from American Chemical Society).

Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

65

in H2O at room temperature for 2 h. Concentration of the solution by warming at 60C for a few minutes, afforded crystals (213, Figure 12b) that revealed an hexameric motif with S3 symmetry where the 9­ methylguanines were located alternately above- and below-the-plane of the six Pt(II) centers. Arakawa et al. reported (01AGE2268) the cyclic hexamer [CpRh(6­ Putrb-N1;N7,S6)]6(CF3SO3)6 (215) with the ligand 6-purinethione ribose (6-putrb), which has a similar ligand skeleton as adenosine, except that the NH2 group in the 6-position is substituted by a thione group. Selfassembly of [M(Cp)(H2O)3]2þ < M = Rh and Ir, isolated from [{M(Cp)­ Cl2}2] (92IC1745) with Ag(CF3SO3) in H2O> and 214 in H2O gave [{Rh(putrb)(Cp)}6](CF3SO3)6 (215a) and [{Ir(putrb)(Cp)}6](CF3SO3)6 (215b) in high yield (Scheme 56a; X-ray crystal structure of 215 (2001AGE2268), reproduced by permission from Wiley-VCH). The crystal structure of 215 (Scheme 56b) revealed a cyclic hexanuclear structure, where the ligand coordinates one Rh(III) ion in a bidentate manner [S and N(7) donors] and bridges to another Rh(III) ion through the N(1) donor. A nucleotide based architecture has been reported by Dalhymple et al. (07IC9945), where the formation of a host complex [Pd(II)(en)(50 -GMP)]4 (50 -GMP = guanosine 50 -monophosphate) was described. Addition of small molecules containing hydrophobic groups resulted in the

Scheme 56

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Monica Soler et al.

expansion of the tetramer to a cyclic hexamer [Pd(II)(en)(50 -GMP)]6 with ˚. an estimated cavity size of 5.2 A

5. CONCLUSIONS The use of heterocyclic species such as furan, pyrrole, thiophene, pyridine, etc., for the preparation of stable, hexameric (macro)molecu­ lar architectures has been demonstrated as a logical pathway to func­ tional materials. This is based, in part, on the mature chemistry and ready availability of these versatile building blocks. Step-wise proce­ dures and self-assembly protocols combined with ingenuity and crea­ tivity have led to the crafting of architecturally controlled species such as Stang’s metal-directed metallocycles, Schlu¨ter’s bipyridine phenyla­ cetylenes, Lehn’s self-assembling helicates, and Newkome’s bisterpyr­ idine-based constructs, to mention but a few. It is clear that the quest for new, utilitarian materials will continue to benefit from the hetero­ cyclic arena.

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Hexameric Macrocyclic Architectures in Heterocyclic Chemistry

06SCI1782

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07IC9945 07ICA1780 07JA14187 07JCD626

08ACR265 08AGE4993 08AM1381 08CC5896 08CEJ223 08CEJ10772 08EJO3328 08IC5197 08JA839

08JA4582 08JA5320

08JOC6037 08OL2091 08T11495

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CHAPTER

2 Metal-Catalyzed Intramolecular Heteroatom (X) ! Carbon (C) Functional Group Migration Reactions Involving Additions of XY Bonds Across Alkynes Nitin T. Patil,a Rahul D. Kavthea and Yoshinori Yamamotob

Contents

1. Introduction 2. Synthesis of O-Containing Heterocycles 3. Synthesis of N-Containing Heterocycles 4. Synthesis of S-Containing Heterocycles 5. Synthesis of Se-Containing Heterocycles 6. Conclusions Acknowledgments References

75 76 83 89 91 92 92 92

1. INTRODUCTION In the last two decades many carbon—carbon and carbon—heteroatom bond-forming reactions have evolved as powerful tools in synthetic organic chemistry. Among them, transition metal-catalyzed cyclization a

Organic Chemistry Division II, Indian Institute of Chemical Technology, Hyderabad 500 607, India;

b

WPI-AIMR (Advanced Institute for Materials Research), Tohoku University, Katahira 2-1-1, Aobaku, Sendai 980-8577, Japan and Department of Chemistry, Graduate School of Science, Tohoku University, Aramaki, Aobaku, Sendai 980-8578, Japan

Advances in Heterocyclic Chemistry, Volume 101 ISSN 0065-2725, DOI 10.1016/S0065-2725(10)01002-0


2010 Elsevier Inc. All rights reserved

75

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Scheme 1 Addition of XH bonds across alkynes.

Scheme 2 Cyclizative functional group migration.

reactions are amongst the most valuable (98MI1, 99MI1, 00CRV2963, 00MI1, 04CRV2127, 04CRV2285, 04CRV2199, 04CRV2239, 04CRV3079, 06MI91). A variety of multiply substituted carbocycles and heterocycles can be obtained by these processes. These reactions are very interesting due not only to their ability to construct complex molecules from readily accessible starting materials but also to the fact that they can be carried out under mild conditions and, in some cases, with high atom economy (91SCI1471, 95AGE259, 00PAC1233). Transition metal-catalyzed annulation of alkynes bearing heteroatoms such as nitrogen, oxygen, and sulfur produces N (88TL1799, 89JOC5856, 89TL2581, 94JOM289, 97TL7687, 98Tl5159, 01JOM149, 02TL1277, 04JOC1126, 04OL1527, 04S610, 05JOC2265, 05OL5437, 05T10958, 06OL3995, 07AGE2074, 07OL627, 07SL1775, 08JOC4160, 09TL2943), O (98TL3017, 99TL431, 00EJO1019, 00JCS775, 03JA15006, 05CEJ5735, 05OL3299, 05OL5409, 06JA3112, 07JOC8559, 07TL1439, 08JOC1620), and S (06AGE1897) containing heterocycles, respectively (Scheme 1). Recently, transition metal-catalyzed cyclizations of alkynes bearing X—Y (X = heteroatom; Y = migratory group) functionality in the proximity have been reported (Scheme 2). The migratory group includes allyl, pro­ pargyl, acyl, (a-alkoxy alkyl), (p-methoxyphenyl)methyl, etc. These reac­ tions are not only mechanistically new but they also are very important from the synthetic point of view. In this review, we highlight such X ! C functional group migration reactions.

2. SYNTHESIS OF O-CONTAINING HETEROCYCLES In 1998, Cacchi and coworkers reported the cyclization of propargylic o-(alkynyl)phenyl ethers 1 promoted by organopalladium complexes (Scheme 3) (98TL5101, 99JOM42, 02EJO2671). The reaction of o-(alkynyl)

Metal-Catalyzed Intramolecular Heteroatom (X) !Carbon (C) Functional Group Migration

Scheme 3

77

Palladium-catalyzed cyclization of propargylic o-(alkynyl)phenyl ethers.

phenyl ethers 1 in the presence of Pd(PPh3)4 and K2CO3 afforded a mixture of 2-substituted-3-allenylbenzo[b]furans 2 and 2-substituted-3­ propargylbenzo[b]furans 3 in good yields. When the aromatic ring of 1 contains an electron-withdrawing group such as COCH3, 2-substituted-3­ allenylbenzo[b]furans 2 was obtained exclusively. The presence of a sub­ stituent on the terminal acetylenic carbon of the propargylic fragment has been found to be mandatory. Mechanistically, Pd(0) adds oxidatively across the C—O bond to form intermediates 4 that can be converted into either 5 or 6 depending on the nature of the R group. Later this approach was extended to the synthesis of 3-allylbenzofurans (98SL741). A seminal work by Balme et al. showed that o-alkynylallyloxybenzenes 7 could also undergo an intramolecular carbo-alkoxylation (07SL1994) reaction which is useful for the synthesis of 2-substituted 3-allylbenzo[b]furans 8 (Scheme 4) (98SL746, 03S2115). In 2000, Fu¨rstner and coworkers reported a platinum-catalyzed intra­ molecular carbo-alkoxylation reaction of substrates of type 11 (Table 1) (00JA6785), (01JA11863). Various tetrahydrofuran derivatives 12 were obtained in good to high yields. The coordination of PtCl2 to the alkyne (cf. 13) has been reported to trigger a cascade comprising a 1,4-addition of the ether oxygen onto the complexed alkyne and simultaneous release of an allyl cation as shown in 14. Union of the allyl cation with the organo­ platinum intermediate then leads to product. They carried out a crossover experiment to gain insight: Does the allyl group migrate inter- or intra­ molecularly? The outcome indicated that no products derived from a crossover of the allyl group were found, thus strongly suggesting an intramolecular delivery of the allyl moieties. This is the first example of an intramolecular carbo-alkoxylation reaction involving an alkyl chain between the alkyne moiety and the heteroatom.

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Scheme 4

Nitin T. Patil et al.

Palladium-catalyzed cyclization of alkynylallyloxybenzenes.

The Yamamoto group reported a PtCl2-catalyzed cyclization reaction of o-alkynylphenyl acetals 15 in the presence of COD to give 3-(a-alkoxyalkyl)benzofurans 16 in good yields (Scheme 5) (05JA15022). Electronic and steric effects on the aromatic ring have an influence on the efficiency of this reaction. The use of an olefin as an additive proved to be necessary to facilitate migration. In the absence of an olefin additive such as COD, lower yields were obtained. It is striking to note that commer­ cially available PtCl2(cod) catalyst did not intervene in the reaction. Therefore, the existence of a platinum oligomer was proposed to be the real active species. Mechanistically, nucleophilic attack of the oxygen atom of the phenyl acetal moiety of 15 onto the PtCl2 coordinated alkyne (cf. 17) occurred to give cyclized intermediate 18 (Figure 1). Migration of the a-alkoxyalkyl group of 18 to the carbon bonded to the platinum atom produced intermediate 19. Removal of the catalyst gave the desired products 16. A successful application of this methodology has been demonstrated for the synthesis of the vibsanol (Scheme 6) (05JA15022), (07T8670). An appropriately designed substrate 20 underwent the carbo­ alkoxylation reaction to form substituted furan 21 that on conventional structural manipulation gave vibsanol 22. A seminal work in Fu¨rstner’s laboratory disclosed the synthesis of C-3-substituted benzofuran 24 by a platinum-catalyzed intramolecular carbo-alkoxylation of 23 (Table 2) (05JA15024). They noticed the necessity of carbon monoxide, which may activate PtCl2. A series of o-alkynyl phenols bearing allyl, Bn, PMB, or MOM-acetals underwent efficient carbo-alkoxylation reactions. This method is not limited only to phenolic substrates: in one example they showed the successful cyclization of

Metal-Catalyzed Intramolecular Heteroatom (X) !Carbon (C) Functional Group Migration

79

Table 1 Platinum-catalyzed intramolecular carboalkoxylation of alkynes Entry

Substrate 11

Product 12

COOMe

1

COOMe O

Yield (%)

59a

O COOMe

2

COOMe O

73a

O

COOMe COOMe

3

71b

O

O CN

4

80c

O

O

CN

COOMe

COOMe

56a,d

O

5

O CN

6

O

O

86e

CN

CN

7

65e

O O

CN

Reaction conditions: A reaction mixture was heated in toluene at 80 �C in the presence of 4–10 mol%of PtCI2. a pure (E)-isomer at the exocyclic double bond. b E:Z = 2.4:1. c E:Z = 1:7.9. d With PtCI4 instead of PtCI2. e Pure (Z)-isomer at the exocyclic double bond.

LnPt

E O 13

E O 14

Pt

benzoic acid ester 25 to isochromones-1-one 26 (Scheme 7) (After comple­ tion of this review Pd-Au catalyzed synthesis of substituted butenolides and isocoumarin was reported) (09JA18022). The potential of this method

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Scheme 5 Platinum-catalyzed intramolecular cyclization-acetal group transfer.

Figure 1 Mechanism for Platinum-catalyzed intramolecular cyclization-acetal group transfer.

Scheme 6 Synthesis of vibsanol.

Metal-Catalyzed Intramolecular Heteroatom (X) ! Carbon (C) Functional Group Migration

81

Table 2 Platinum-catalyzed intramolecular carboalkoxylation of alkynes

Scheme 7 Platinum-catalyzed intramolecular carboalkoxylation of benzoate.

has been demonstrated in the synthesis of the natural product erypoegin H. Treatment of an appropriately substituted alkyne 27 with a catalytic amount of PtCl2 under a CO atmosphere furnishes precursor 28 in 84% yield. The precursor 28 was converted into erypoegin H 29 after synthetic structural manipulations (Scheme 8) (07AGE4760). The Pt(II)-catalyzed processes described by Yamamoto and Fu¨rstner are clearly advantageous compared to Cachhi’s palladium-catalyzed protocol. Cachhi’s procedure is amenable only to o-alkynylphenols bearing an allyl group and is not useful to acetalic substrates as the Pd(0) species is unable to generate a catalytically competent component

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Scheme 8 Synthesis of erypoegin H.

by oxidative addition. Moreover, bromo-substituents are tolerated under Pt(II) catalysis whereas they are not expected to be tolerated under Pd(0) catalysis. Recently, Nakamura and coworkers reported the synthesis of substituted cyclic enol ethers 31 and 32 via the intramolecular carbo­ alkoxylation of alkynes 30 using PtCl2 catalyst in the presence of 1,5-hexadiene (Table 3) (08OL309). The reaction in the absence of 1,5-hexadiene did not proceed at all, and therefore they propose the presence of oligomeric platinum that could be obtained by the disconnec­ tion of Pt—Cl bonds in polymeric PtCl2 by the olefin additive. The Z/E Table 3 Synthesis of substituted cyclic enol ethers via platinumcatalyzed intramolecular carbo-alkoxylation of alkynes

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83

Scheme 9 Bismuth-catalyzed carbo-oxycarbonylation of alkynes.

selectivity is dependant on the electronic property of the estergroup; substrates having an electron-deficient ester group afforded Z isomers as major product, while those having a relatively electron-rich ester group gave E isomers. Later, Takaki et al. have shown that not only typical transition metal complexes but also borderline metal complexes have the ability to pro­ mote analogous reactions. They reported the synthesis of substituted lactones 34a–e by a bismuth-catalyzed carbo-oxycarbonylation of alkynyl ester 33 (Scheme 9) (08OL5119). A crossover experiment showed that the reaction is intramolecular, and this observation is in agreement with the results reported by Fu¨rstner et al. (01JA11863).

3. SYNTHESIS OF N-CONTAINING HETEROCYCLES In 1998, Cacchi et al. reported the synthesis of C-3-substituted indoles via intramolecular carboamination of alkynes. The reaction of o-alkynyltri­ fluoroacetanilides 35 in the presence of catalytic amounts of Pd(PPh3)4 and excess K2CO3 in CH3CN at 90C gave C-3-substituted indoles 36 and/or 37 (Table 4) (98JOC1001). The platinum-catalyzed cyclization of o-alkynyl aryl amides 38 pro­ vides the synthesis of 3-substituted indoles 39 (Table 5) (04JA10546). In most cases, small amount of 3-unsubstituted indoles 40 was obtained. This reaction is strongly influenced by solvents; aromatic solvents con­ taining an electron-donating group enhanced the rate. Mechanistically, the coordination of PtCl2 to the alkyne increases the electrophilicity of alkynes, which in turn results in the attack of a tethered nitrogen atom to form zwitterionic intermediate 41. An intramolecular [1,3]-migration of the acyl moiety then yields intermediate 42, which produces indole 39 and PtCl2 is regenerated. Later, they reported the cyclization of o-alkylphenyl ureas 43 and o-alkylphenyl carbamates 46 for the synthesis of indoles (44 and 45) (Table 6) and indole-3-carboxylates (47a–b), respectively (Scheme 10) (09TL2075).

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Table 4

Nitin T. Patil et al.

Palladium-catalyzed cyclization of o-alkynyltrifluoroacetanilides

Table 5 Platinum-catalyzed cyclizative carbonyl group migration

In 2005, Fu¨rstner et al. reported the synthesis of substituted indoles 49a–b by platinum-catalyzed intramolecular carboamination of alkynes 48 (Scheme 11) (05JA15024). In 2007, Malacria and coworkers designed a

Metal-Catalyzed Intramolecular Heteroatom (X) ! Carbon (C) Functional Group Migration

85

Table 6 Platinum-catalyzed cyclizative amide group migration

Scheme 10

Platinum-catalyzed cyclizative ester group migration.

Scheme 11

Platinum-catalyzed Intramolecular carboamination of alkynes.

substrate of type 50 for the synthesis of functionalized indoles 51 and 52 (Tables 7 and 8) (07AGE1881). Interestingly, they found that the reaction is not only catalyzed by PtCl2 but also by Bro¨ nsted acids such as SiO2 and p-TSA is also equally effective. A ratio of regioisomeric 51:52 depends upon the nature of the R group and the reaction temperature. Since Bro¨ nsted acids catalyze the reaction (09JCS(CC)5075), a mechanism invol­ ving a proton-mediated hydroamination/3-aza-Cope rearrangement cas­ cade was proposed.

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Table 7 Synthesis of indoles via intramolecular carboamination of alkynes

Table 8 Synthesis of indoles via intramolecular carboamination of alkynes

Nakamura et al. reported the gold-catalyzed intramolecular amino­ sulfonylation (formal addition of an N—S bond to a triple bond) for the synthesis of 3-sulfonylindoles 57 (Table 9) (07AGE2284, 08MI285). The procedure involved the treatment of o-alkynyl-N-sulfonylanilines 56 with AuBr3 catalyst in toluene at 80C for 1 h. The formation of small amounts of 58 and 59 was also observed. It is interesting to note that the use of InBr3 as a catalyst instead of AuBr3 gave 6-sulfonylindoles 58 as the major products.

Metal-Catalyzed Intramolecular Heteroatom (X) ! Carbon (C) Functional Group Migration

87

Table 9 Gold-catalyzed cyclizative sulfonyl group migration

Stevens and coworkers designed a substrate of type 60 for the synth­ esis of 1-cyanoisoindole 61. In the presence of 1 mol% AuCl3, a series of aminonitriles 60 underwent 5-exo-dig cyclization followed by 1,3-alkyl group migration (Table 10) (09OL5018). They observed that Table 10 Synthesis of 1-cyanoisoindole via gold-intramolecular carboamination of alkynes

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Scheme 12 Kinetic selectivity in gold-catalyzed intramolecular carboamination of alkynes.

differentiation can be made between two migrating groups with different sterical demand, albeit in poor selectivity. At room temperature a 50:50 mixture of 63 and 64 was obtained, while at -78C a selectivity up to 63% in a favor of 63 was achieved (Scheme 12). The same research group reported the synthesis of phosphonylated substituted isoindoles 66 under a microwave condition from o-ethynylbenzyl a-aminophosponates 65 (Table 11) (07OL465). Note that the process is thermally driven and therefore no catalyst was necessary. Gagosz and coworkers utilized the carbo-amination process for the synthesis of functionalized pyrroles 68 by using a gold-catalyzed cycliza­ tion of allyl tosylamides 67 (Table 12) (07OL3181). The reaction is reported to proceed at room temperature using the air-stable crystalline Ph3PAuNTf2 catalyst, which was discovered by them (05OL4133).

Table 11 Synthesis of phosphonylated substituted isoindoles under microwave conditions

Metal-Catalyzed Intramolecular Heteroatom (X) ! Carbon (C) Functional Group Migration

89

Table 12 Synthesis of pyrroles via intramolecular carboamination of alkynes

4. SYNTHESIS OF S-CONTAINING HETEROCYCLES The gold-catalyzed intramolecular carbothiolation of alkynes for the synthesis of 2,3-disubstituted benzothiophene was reported by Naka­ mura and coworkers (Table 13) (06AGE4473). The reaction involves the migration of groups such as a-alkoxy alkyl, PMB, and allyl from the

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Table 13 Synthesis of thiophenes via intramolecular carbothiolation of alkynes

sulfur atom to the alkyne. Various thiophene derivatives 70 were obtained from readily available 69. Concerning the accessibility of C-3­ substituted thiophenes, this method is superior to the known FriedelCrafts and lithiation/electrophile-trapping reactions. The same groups reported the synthesis of the gold-catalyzed carbothiolation reaction of 71, which proceeds with 1,3-migration of an aryl ethyl group with reten­ tion of configuration at the migrating group to give enantiomerically enriched 72 (Table 14) (08OL2649). Pioneering work from Nakamura’s laboratory revealed the synthesis of 3-silylbenzo[b]thiophenes 74 using gold-catalyzed cyclization of (o-alkynylphenylthio)silanes 73. The reaction proceeds through thiosily­ lation and 1,3 migration of the silyl group (Scheme 13) (07OL4081). For example, 73 in the presence of 2 mol% AuCl in toluene at 45C gave 3-silylbenzo[b]thiophene 74a–e in good to excellent yields. The reaction is reported to proceed through the intramolecular capture of the vinyl gold intermediates by the silicon electrophiles (cf. 75).

Metal-Catalyzed Intramolecular Heteroatom (X) ! Carbon (C) Functional Group Migration

91

Table 14 Chirality transfer in gold-catalyzed carbothiolation of alkynes

Scheme 13 Synthesis of 3-silylbenzo[b]thiophenes via intramolecular thiosilylation of alkynes.

5. SYNTHESIS OF Se-CONTAINING HETEROCYCLES Similar to oxygen, nitrogen, and sulfur nucleophiles, selenium can also be used in this type of reaction. Very recently, a platinum-catalyzed carbo­ selenation reaction has been reported. In the presence of 2 mol% PtCl2, alkynes 76 in toluene at 25C gave 2,3-disubstituted benzo[b]seleno­ phenes 77 (Table 15) (09JOC5509). Table 12 shows that a benzyl group on selenium is reluctant to migrate (entry 7) while a strong cation-stabilizing group is best for migration (entries 1—6).

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Table 15 Synthesis of benzo[b]selenophenes via intramolecular carboselenation of alkynes

6. CONCLUSIONS In the past decade, alkynes have become attractive starting material for the synthesis of a variety of synthetically useful products. Generally, this type of reaction relies on the interaction of a metal catalyst with the p-bond of the alkynes (07ARK6, 07ARK121, 07AGE3410, 08CRV3239, 08CRV3266, 08CRV3351, 08CRV3395, 08S3183, 09MI1). Most of the reac­ tions involve a single starting material containing various functional groups strategically positioned along a chain, terminating with alkyne functionality. Recent literature revealed that a new type of reactivity is exhibited by the metal catalysts, that is, X! C functional group migra­ tion reactions. The results presented herein suggest that a cationstabilizing group such as allyl, propargyl, acyl, (a-alkoxy alkyl), and (p-methoxyphenyl)methyl have an ability to migrate from a heteroatom to a carbon atom.

ACKNOWLEDGMENTS NTP gratefully acknowledges financial support by the Council of Scientific and Industrial Research, India. NTP is also grateful to Dr. J. S. Yadav, Director, IICT, and Dr. V. V. N. Reddy, Head, Org-II Division, for their support and encouragement.

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05JOC2265 05OL3299 05OL4133 05OL5409 05OL5437 05T10958 06AGE1897 06AGE4473 06JA3112 06MI91 06OL3995 07AGE1881 07AGE2074 07AGE2284 07AGE3410 07AGE4760 07ARK6 07ARK121 07JOC8559 07OL465 07OL627 07OL3181 07OL4081 07SL1775 07SL1994 07T8670 07TL1439 08CRV3239 08CRV3266 08CRV3351 08CRV3395 08JOC1620 08JOC4160 08MI285 08OL309 08OL309 08OL2649

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08OL5119 08S3183 09JA18022 09JCS(CC) 5075 09JOC5509 09MI1 09OL5018 09TL2075 09TL2943

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CHAPTER

3 Biindolyls David StC Black and Naresh Kumar

Contents

1. Introduction 2. Synthesis 2.1 Formation of two indole rings by cyclization 2.2 Formation of one indole ring by cyclization 2.3 Linkage of two indole rings by coupling reactions 3. Reactions 4. Conclusion References

97 98 98 100 103 116 120 121

1. INTRODUCTION The aim of this chapter is to survey the synthesis and reactions of biindolyls, and in doing so, to highlight the significant structural types that have been overlooked or underdeveloped in the past. The connection of indole rings can lead to 28 structural isomers by the variation of linkage possible. Thus the following types can be envisaged, going around the ring in turn. Linkage at N1: This can give rise to 1,1�-; 1,2�-; 1,3�-; 1,4�-; 1,5�-; 1,6�-; and 1,7�­ biindolyls. Linkage at C2: This can additionally give rise to 2,2�-; 2,3�-; 2,4�-; 2,5�-; 2,6�-; and 2,7�-biindolyls. Linkage at C3: This can additionally give rise to 3,3�-; 3,4�-; 3,5�-; 3,6�-; and 3,7�-biindolyls. School of Chemistry, The University of New South Wales, UNSW Sydney, NSW 2032, Australia Advances in Heterocyclic Chemistry, Volume 101 ISSN 0065-2725, DOI 10.1016/S0065-2725(10)01003-2

� 2010 Elsevier Inc. All rights reserved

97

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David StC Black and Naresh Kumar

Linkage at C4: This can additionally give rise to 4,4�-; 4,5�-; 4,6�-; and 4,7�­ biindolyls. Linkage at C5: This can additionally give rise to 5,5�-; 5,6�-; and 5,7�­ biindolyls. Linkage at C6: This can additionally give rise to 6,6�-; and 6,7�-biindolyls. Linkage at C7: This can additionally give rise to 7,7�-biindolyls. The first 7 examples listed contain a C—N linkage and the remaining 21 examples contain C—C linkages. Many of these types of biindolyls are either unknown or poorly known. Also the synthetic methods often lead to mixtures of structural isomers. Consequently the review will not be based on a systematic consideration of each structural isomer, but rather focus on the synthetic routes involved. A following section on some representative reactions of biindolyls will also be included.

2. SYNTHESIS 2.1 Formation of two indole rings by cyclization One of the oldest methods of indole synthesis is the Madelung cycliza­ tion of a 2-amidotoluene under conditions of very strong base and high temperature. Because of the harsh conditions, the method is not com­ patible with sensitive functional groups. However, one of the most successful examples is the cyclization of the oxamide 1 to 2,2�-biindolyl 2 in 80% yield under the precise influence of potassium tert-butoxide at 300�C (95T5631). These conditions represent a significant improvement on the original work of Madelung, which achieved a yield of 26% using sodium pentoxide at 360�C (12CB1128, 14LA58). The Madelung type of synthesis can be modified by the introduction of activating influences, as shown by the milder cyclization of the oxamide phos­ phonium salt 3 with potassium tert-butoxide in refluxing toluene: how­ ever the yield of the 2,2�-biindolyl 2 in this case is only 12% (84JHC623, 88CB2259) (Scheme 1). Another standard indole synthesis involves cyclization of a 2­ alkynylaniline derivative, and this can be doubled up to generate the parent 2,2�-biindolyl 2. Treatment of the carbamic ester 4 with sodium ethoxide in refluxing ethanol gives the biindolyl 2 in 86% yield (95SL859), while a gold(III)-catalyzed process converts the diamino­ dialkyne 5 into biindolyl 2 (04S610) (Scheme 2). More highly functio­ nalized 2,2�-biindolyls have also been successfully prepared by this method (06TL6385).

99

Biindolyls

Me O N H

H

N

O Me

t-BuOK, 300 °C

1

80%

PPh3

t-BuOK, toluene, heat

O N H

H N

H N N H 2

12%

O PPh3 3

Scheme 1

EtO2C NH

NaOEt, EtOH, heat

4

HN

CO2Et

86%

NaAuCl4.3H2O, EtOH, H2O NH2

H N N H 2

H2N 5

Scheme 2

Simultaneous construction of three rings affords the indolocarbazole 8 by combination of the dialkyne 6 with a dibromomaleimide derivative 7 under the catalytic influence of tetrakis-triphenylphosphinepalladium (95TL7841) (Scheme 3). In a rather special case, the reaction of N-methylformanilides 9 with phosphoryl chloride gives low yields of 3,3�-diarylamino-2,2�-biindolyls 11, via the cyclization of the double iminium salts 10 (98JCSP(1)1619) (Scheme 4).

100

David StC Black and Naresh Kumar

F3COC NH

O

CH2Ph Pd(Ph3P)4 N O K2CO3, MeCN

O

CH2Ph N O

+ Br 6

52%

Br

HN COCF3

N H

7

N H 8

Scheme 3

X

X N

X

X CHO N Me 9 X = F, Cl, Br

Me

POCl3

Cl

O

N Me

N Me

N

Me N Cl Me

Me

X X

N

N Me

Me N X

Me

N

X

17–28% 10

X

11

Scheme 4

In principle, any indole synthesis involving a cyclization process can be adapted to the formation of biindolyls, provided that a suitable pre­ cursor is readily available. Indeed, 2,5�-, 3,5�-, and 5,5�-biindolyls have been prepared in modest yields by double Fischer syntheses involving the cyclization of bis-hydrazones formed from ethyl pyruvate and bis-hydra­ zines of biphenyl compounds (78KGS217, 90KGS343, 92KGS1336). Considerable scope remains for the development of this synthetic strategy.

2.2 Formation of one indole ring by cyclization This is a much more popular strategy than the previous one, because indoles can be readily functionalized. Furthermore, this strategy allows for the formation of unsymmetrical biindolyls. 2,2�-Biindolyls can be formed by the Fischer synthesis that combines a 2-acylindole with an arylhydrazone. For example, the cyclic 2-acylindoles 12 react with arylhydrazines in refluxing trifluoroacetic acid and acetic acid to give the pentacyclic heteroaromatic systems 13 containing a 2,2�­ biindolyl linkage (98SC1239) (Scheme 5).

101

Biindolyls

PhNHNH2 CF3CO2H, CH3CO2H reflux

S R N H

24–54%

O

12

S

R N H

N H 13

R = H, MeO, Me, Br, Cl

Scheme 5

Me O

Me

PhNHNH2 HOAc, reflux

N

CHO

DDQ, dioxan reflux

H N

N

N

14

H N

15

16

Scheme 6

In a related process, a different cyclic 2-acylindole 14 combines with phenylhydrazine in refluxing acetic acid to give a 91% yield of the 2,2�­ biindolyl 15. This compound was subsequently oxidized by dichlorodi­ cyanoquinone to generate the naturally occurring homofascaplysin C 16 (96TL5207) (Scheme 6). A related process gives a modest yield of a fused 2,2�-biindolyl (95T12797). The reductive cyclization of 2-nitrostyrenes is a useful method for the formation of indoles. When applied to indolyl-2-nitrostyrenes, such as 19, the 2,2�-biindolyl 20 can be formed (03OL3721) (Scheme 7). The sequence of reactions can be carried out in one pot, by the combination of indole-2­ carbaldehyde 17 and the nitrobenzene 18 to generate the intermediate nitrostyrene 19, which can be reduced by either palladium acetate and

Cl CHO N SO2Ph 17

TMS

+

O 2N

1. TBAF 2. TFAA 3. DBU 85%

NO2

N SO2Ph

18

Cl 19

Pd(OAc)2, PPh3 or P(OEt)3

H N N SO2Ph 20

Scheme 7

96% Cl

102

David StC Black and Naresh Kumar

O2N CHO Cl +

21

1. TBAF 2. TFAA 3. DBU

TMS

N SO2Ph

Cl

60%

NO2

N SO2Ph

18

22 Cl Pd(OAc)2, PPh3, or P(OEt)3

HN

71% N SO2Ph 23

Scheme 8

triphenylphosphine, or triethylphosphite to give the 2,2�-biindolyl 20 (01T5199). Suitable examples have subsequently been converted into members of the naturally occurring tjipanazole family. A similar process commencing with the indole-3-carbaldehyde 21 affords the 2,3�-biindolyl 23 via the intermediate 22 (03OL3721) (Scheme 8). 3,3�-Indoloquinones have been formed through an oxidative cycliza­ tion process. For example, N-methyltryptamine 24 combines with 2-methoxynaphthoquinone 25 to give the intermediate 26, which on treatment with dichlorodicyanoquinone in acetic acid gives the 3,3�-indoloquinone 27 (98TL7677) (Scheme 9). The N-desmethyl analog of intermediate 26 could not be cyclized. Some 3-arylacetylindoles 28 can be nitrated in the appropriate ortho position to give the nitroketones 29, which undergo reductive cyclization with either stannous chloride in hydrochloric acid or sodium hydrosulfite to afford the 2,3�-biindolyls 30 (62JOC507) (Scheme 10). The sequence is limited by the ability to nitrate in the desired position, so is not widely applicable (64JOC2030). A modified Bischler indole synthesis can be used to prepare 4,6­ dimethoxy-3-arylindoles. The 2,3-diphenyl-4,6-dimethoxyindole 31 can be acetylated at C7 and the acetyl compound 32 converted via the bro­ moketone 33 into an arylaminoketone 34, which can be cyclized to a 3,7�­ biindolyl 35 (94AJC1741) (Scheme 11). Benzo[b]carbazoles can be synthesized readily and in good yields from the combination of 2,3-unsubstituted indoles and o-phthaldialde­ hyde 37 in the presence of acid catalysts. Use of phosphoryl chloride in

103

Biindolyls

O

NHMe

Me

O MeO

N

EtOH reflux

+

O

91%

N H

O

N H

25

24

26

DDQ, HOAc Me N

O 78%

O N H 27

Scheme 9

NH

MeO O MeO 28

HNO3, HOAc

MeO

76%

MeO

R

NH O NO2

R

SnCl2 or MeO Na2S2O4 28–54%

MeO

29

N H

NH R

30

R = H, Me

Scheme 10

chloroform gives rapid reactions and indole 36 yields 11-(3-indolyl)benzo [b]carbazole 38 (effectively a benzannulated 3,4�-biindolyl), whereas the reaction using p-toluenesulfonic acid in methanol proceeds slowly and yields the isomeric 6-(3-indolyl)benzo[b]carbazole 39 (effectively a ben­ zannulated 3,7�-biindolyl) (99TL6653) (Scheme 12).

2.3 Linkage of two indole rings by coupling reactions Biindolyls can readily be formed by the direct combination of two indoles or related cyclic systems, using a variety of substitution, metal-catalyzed coupling, or oxidative processes. An early example involved the Lewis acid-catalyzed combination of a 3-substituted indole with its singlet oxy­ gen indoline product to give a 2,2�-biindolyl. This is illustrated in the case of tryptophol 40 undergoing conversion to the 3-hydroxyindoline 41, followed by combination of the two species to give the 2,2�-biindolyl 42 in 52% yield (82JCS(CC)977) (Scheme 13).

104

David StC Black and Naresh Kumar

MeO

MeO

Ph Ph N H

MeO

Ph N H

MeO

88%

MeO

Ph

Me2NCOMe

POCl3

Me

Ph

CuBr2

Ph N H

MeO

70%

O

O Br

31

32

33 NH2

OMe

MeO 95% MeO

MeO

Ph 1. TFAA, Et3N 2. TFA reflux 3. KOH, MeOH

Ph N H

MeO MeO

Ph Ph N H

MeO O

56% NH NH

MeO

MeO MeO

35

34

Scheme 11

H N

POCl3 58% N H

OHC

+

N H

38

OHC p-TsOH 79%

36

37

N H 39

N H

Scheme 12

When indole is treated with acid it forms an indoleninium salt, which is electrophilic at C2 and can then be attacked by another indole to give a 3-indolyl-indoline (61JCS940). However, it is not easy to oxidize these compounds to 2,3�-biindolyls. 3-Substituted indoles undergo similar

105

Biindolyls

OH

OH HO

1O

1. 2 2. NaBH4

O

90%

N H

N H

H N

40, TiCl4 52%

N H HO

40

41

42

Scheme 13

acid-catalyzed dimerization to give indolyl-indolines with a 2,2�-linkage, and these can subsequently be converted, with some difficulty, into 2,2�-biindolyls (60TL13; 72JCS(P1)418). For example, 4,6-dimethoxy-3­ methylindole 43 on treatment with hydrogen chloride gas in ether yields the 2,2�-indolyl-indoline 44, which can be formylated using the Vilsmeier reagent to give the formyl-formamide 45 (80TL1883, 83AJC2407). A sequence of chloranil oxidation, amide hydrolysis, and further formylation effectively gave the 2,2�-biindolyl-7,7�-dicarbaldehyde 46 (85JCS(CC)1174, 93SL246) (Scheme 14). However, when 2-chloro-3-methylindole 47 is com­ bined with 3-methylindole 48 in the presence of boron trifluoride etherate, the 2,2�-biindolyl 49 is formed directly in 89% yield (81H1441) (Scheme 14). MeO

MeO

Me

Me

H2 N

HCl, ether 70%

N H

MeO

N H

MeO

Cl OMe

H H Me OMe

43 44

1. Chloranil 2. POCl3, DMF

MeO

Me

MeO CHO

N H

MeO

CHO

H N

OMe

POCl3, DMF MeO

Me

CHO

OMe

Me

Me

N H 47

N H

OMe

H H Me OMe 45

46

Cl

CHO N

Me

Me

H N

BF3.OEt2

+ N H

89%

48

N H

Me 49

Scheme 14

106

David StC Black and Naresh Kumar

2,3�-Biindolyls can be formed directly by the acid-catalyzed combina­ tion of 3-unsubstituted indoles with 3-bromoindoles, as shown by the formation of the parent 2,3�-biindolyl 51 in 85% yield from 3-bromoindole 50 and indole 36 (83JCS(CC)1074, 84T3251) (Scheme 15). The reaction has wide generality and has been extended to the formation of trimeric structures (86T5019, 89JCSR277). In a modification of the Vilsmeier reagent, phosphoryl chloride and 2-indolinone combine to form an electrophile that can undergo reaction with indoles to yield a wide variety of biindolyl products (80T1445). Reaction of 2-phenylindole 52 with this reagent gives the 2,3�-biindolyl 53 and the 2,3�; 2,3�-terindolyl 54 in 60% and 19% yields, respectively (84JCS(CC)441, 96T4697, 98ANH85) (Scheme 16). The related Br

TFA

+

N H

N H

50

85%

NH

N H

36

51

Scheme 15

O

H N

N

H

Ph N H

NH

NH

POCl3

+ Ph

Ph

N H 52

53

N H 60%

54

19%

MeO

MeO

O N H

Ph N H

MeO

Ph MeO

POCl3

N H

MeO

NH +

NH

Ph N H

MeO

56% 55

25%

56

57 MeO

MeO

Ph N H

MeO

Ph

O

Ph N H

Ph N H

MeO POCl3 NH

75% 58

59

Scheme 16

107

Biindolyls

4,6-dimethoxy-2-phenylindole 55 under similar conditions gave the 2,3�­ biindolyl 56 and the 2,7�-biindolyl 57 in respective yields of 56% and 25%. When reactivity at C3 is blocked, as in the case of 4,6-dimethoxy-2,3­ diphenylindole 58, only the 2,7�-biindolyl 59 is obtained in 75% yield. The situation is a little different with 3-substituted-4,6­ dimethoxyindoles. Despite the reactivity of these compounds, mixtures of 2,2�- and 2,7�-biindolyls are formed in only relatively low yields and are dependent on the nature of the 3-substituent. However, the replacement of phosphoryl chloride with triflic anhydride leads to regioselective formation of the 2,7�-biindolyl in high yield, as illustrated by the conversion of the bromophenylindole 60 into the 2,7�-biindolyl 61 in 99% yield (96T4697) (Scheme 17). On the other hand, the corresponding methoxyphenylindole 62 Br Br MeO MeO

O N H N H

MeO

N H

MeO NH

(CF3SO2)2O 99%

60

61

OMe

OMe MeO MeO

O N H N H

MeO

N H

MeO

N H

NH

(CF3SO2)2O, 2 equiv. 50%

62

63 O N H

MeO CO2Me N H

MeO

(CF3SO2)2O 68%

64

NH MeO CO2Me MeO

N H 65

Scheme 17

108

David StC Black and Naresh Kumar

is sufficiently reactive to combine with two equivalents of the reagent to form the 2,2�; 2,7�-terindolyl 63 in 50% yield. Under triflic anhydride condi­ tions, methyl 5,6-dimethoxyindole-2-carboxylate 64, being 2­ substituted, directs the incoming electrophile to C3 to give the 2,3�-biindolyl 65 in 68% yield (04TL7273) (Scheme 17). Substituted indolones have been investigated in connection with this synthetic strategy, but the results are mixed (96T7003, 04TL7273). For example, when the 2,3-diphenylindole 58 is reacted with 4,6­ dimethoxy-2-indolinone and phosphoryl chloride, a 30% yield of the 2,7�; 2,7�-terindolyl 67 is obtained in addition to a 55% yield of the expected 2,7�-biindolyl 66 (96T4697). The corresponding reaction involving 3­ methyl-2-indolinone afforded the 2,7�-biindolyl 68 in 71% yield (96T7003). Application of the more complex 4,6-dimethoxy-3-spirodithio­ lan-2-indolinone gave the 7,7�-biindolyl 69 in 50% yield, following rear­ rangement of the dithiolan ring (Scheme 18). Indole 36 readily reacts with isatin 70 in the presence of dimethyla­ mine to give the alcohol 71, which can be reduced with diborane to 3,3�­ biindolyl 72 in 58% yield (96TA285) (Scheme 19). This approach has been MeO

MeO MeO

MeO Ph N H

MeO

Ph Ph

Ph

O

Ph

MeO

Ph

N H

NH

+

NH

POCl3

N H

MeO

N H

MeO

H N

OMe

MeO OMe 58

66

55%

67 MeO

30%

Ph

Me

MeO

Ph

Ph O N H

Ph N H

MeO

N H

MeO Me

NH

POCl3

71%

58

68 MeO

MeO

MeO

S

S O

Ph

MeO

Ph

N H POCl3 50%

58

S S

OMe 69

Scheme 18

N H OMe

MeO H N

Ph N H

MeO

Ph

OMe

109

Biindolyls

HN

O Me2NH +

B2H6

O

N H

HN

O OH

N H

58% N H

70

36

N H 72

71 HN

+

NO2 N SO2Ph

N H

N

NaH, THF +

73

36

NO2

NO2

N H

N H 74

11%

75

29%

Scheme 19

developed with modest functionality to provide precursors for indolo­ carbazoles (98JCS(P1)2009). Indole also behaves as a nucleophile in a base-induced Michael addition to the 2-nitroindole 73 to give a mixture of the 3,3�-biindolyl 74 and the 1,3-biindolyl 75 in low yields (99TL7615) (Scheme 19). Palladium-catalyzed coupling reactions have been widely used to generate biindolyl systems. The 3-indolylzinc compound 76 can be coupled with the 3-bromoindole 77 to give the 3,3�-biindolyl 78 in 55% yield (94TL793) (Scheme 20). Related indolyl Grignard reagents and iodoindoles can also be used with palladium catalysis (04T3695), but related indolyl copper species react directly with iodoindoles without palladium catalysis (80T1439). The palladium-catalyzed homocoupling of dimethyl indol-2-ylborates such as 79 generates 2,2�-biindolyls such as 80 (97TL7661, 01T5199) (Scheme 21). Such borate esters can also combine with iodoindoles, and for example, 2-iodoindole 81 gives an unsymmetrical 2,2�-biindolyl 82 in 67% yield. The Suzuki—Miyaura coupling strategy has recently been extended to deliver a wide range of homo- and hetero-biindolyls (08JOC9177, 10H1267). For instance, the 3-bromoindole 83 was converted into the PhO2S

ZnCl

Br +

N TBDMS 76

N

PdCl2(Ph3P)2 dibalH

N SO2Ph

77

Scheme 20

55%

78

N TBDMS

110

David StC Black and Naresh Kumar

Bn N

(Ph3P)4Pd, Na2CO3 toluene, reflux B(OMe)2 N Bn

N Bn

79

B(OMe)2 N

Bn

I

79

N Bn

67%

81 Br

MeO CO2Me N Bn

MeO

H N

(Ph3P)4Pd, Na2CO3 toluene, reflux

N H

+

80

82 B(pin)2

Pd2(dba)3 MeO HB(pin)

CO2Me

Bn 80, [Pd] base

N Bn

XPhos, base MeO 84%

67%

CO2Me N Bn

84 B(OH)2

CO2Me OH N H

85 CO2Me

Pd(OAc)2, SPhos K3PO4, dioxan

OH

+ N SO2Ph

I 86

OMe

MeO MeO

83

OMe

N MeO2C

87

82%

N H 88

N H

Scheme 21

boronate 84 and the two coupled to give the 3.3�-biindolyl 85 (Scheme 21). The application of related 4-bromo- and 7-bromoindoles increases the scope of this strategy, and biindolyls with 3,3�-, 3,4�-, 4,4�-, 3,7�-, 4,7�-, and 7,7�-linkages can be prepared in modest to good overall yields. The Suzuki—Miyaura coupling between an indolyl-3-boronic acid 87 and a 1-iodocarbazole 86 to give a 1-(3-indolyl)carbazole 88 (effectively a benzannulated 3,7�-biindolyl) is a key step in the total synthesis of the yeast metabolite pityriazole (08OBC2481) (Scheme 21). Another route involving palladium coupling is the intramolecular indole—indole coupling of N, N�-carbonyl-bis-indoles 89–90 with palladium (II) acetate in acetic acid to give the biindolyls 91–92 in good yield: base hydrolysis converted these intermediates into the 2,2�-biindolyls 2 and 93 (80T1439, 85JCS(CC)1174) (Scheme 22). This intramolecular coupling strategy has been used to great effect in the synthesis of indolocarbazoles of biological interest. Two indole units can be coupled at C3 with a succinimide moiety to give compounds such as 94, which can then be coupled with palladium chloride to give indo­ locarbazoles such as 95 (93TL8361, 96T8099, 07TL7399) (Scheme 23). Aryl—aryl coupling has been effectively induced in a related di-indolyl succinic anhydride by irradiation with ultraviolet light in the presence of iodine (94S25, 94TL5555).

111

Biindolyls

R

R

R

R

Pd(OAc)2, HOAc N R

N

N

65–84% R

R

O 89 : R = H 90 : R = OMe

KOH EtOH R

H N

R

O

91 : R = H 92 : R = OMe 60–89%

R

N H

R

N

R

2 : R=H 93 : R = OMe

Scheme 22

H N

O

O

H

N

O

O

PdCl2, DMF 80%

N H

N

H

N H

94

N H 95

Scheme 23

It was found in the course of the above research that a direct oxidative coupling, for example, with dichlorodicyanoquinone gave even higher yields of products. Oxidative coupling has played an important part in the formation of biindolyls, and this strategy will now be considered. One of the earliest oxidative approaches was to exploit indigo 96, itself an oxidation product of indoxyl (3-indolinone), with a 2,2�-linkage. In prin­ ciple, it should then be possible to convert it by a reductive process into a 2,2�-biindolyl. This has proven to be not straightforward. The most effective conditions appear to be the treatment of indigo 96 with tin powder and acetic anhydride in acetic acid at 64—66�C: the product is the monoacetoxy­ lated 2,2�-biindolyl 97 in 85% yield (97H1647, 99H1233, 04H483) (Scheme 24). This product has served as an important starting material for some naturally occurring indolocarbazoles (85TL4015, 07TL231). The related dia­ cyloxy compounds can be prepared via the leucoindigo sodium salt, obtained by reduction of indigo with zinc dust in ethanol, followed by treatment with sodium hydride and phenylacetyl chloride. This method is most effective with bulky acyl halides, such as phenylacetyl chloride, which gives 98 in ~80% yield (84JCS(P1)2305) (Scheme 24).

112

David StC Black and Naresh Kumar

O

OAc

H N

Sn, Ac2O, HOAc 85%

N H

N H

O 96

O

N H

H N

97 1. Zn, EtOH

2. NaH, THF 3. PhCH2COCl

H N

PhCH2COO

N H

80% O 96

H N

OCOCH2Ph 98

Scheme 24

S DMF N H

59%

1. LiAlH4 2. MeI HN

Raney Ni

NH S

36

HN

HN MeS

40% SMe

S

S S

99

100

N H

72

N H

Scheme 25

Indole 36 has been reacted with sulfur to give a new cyclic tetrasulfide 99 with a 3.3�-linkage. On treatment with lithium aluminium hydride followed by methyl iodide, the 2,2�-dithiomethyl-3,3�-biindolyl 100 is obtained and the thiomethyl groups can be removed with Raney nickel to yield the parent 3,3�-biindolyl 72 (60JA2739) (Scheme 25). The activated 4,6-dimethoxyindoles, if substituted at both C2 and C3, undergo ready oxidation at C7 to yield 7,7�-biindolyls: for example, the 2,3-diphenylindole 58 gave a quantitative yield of the 7,7�-biindolyl 101 on oxidation with 1,4-benzoquinone (89JCS(CC)111, 94T10497, 05T10490) (Scheme 26). The related N-methylindole failed to dimerize under these conditions, presumably for steric reasons. The 7,7�-biindolyl 101, and some related 2-methyl-3-phenyl analogs, can be formed by reaction with cold, concentrated nitric acid in acetonitrile. These conditions also generate 2,2�-biindolyls, such as 103 by oxidative coupling of N­ methylindoles, such as 102: the N-substitution is essential for successful coupling (05T853) (Scheme 26). Thallium (III) trifluoroacetate is also an effective oxidative coupling reagent, and the N-phenylsulfonylindole 104 gives a 70% yield of the 2,2�­ biindolyl 105 (08T7787) (Scheme 27). Unfortunately removal of the

113

Biindolyls

MeO MeO

Ph Ph

Ph O

O

Ph N H

MeO

N H OMe

MeO H N Ph

100%

Ph 58

OMe

101 Br Br MeO

HNO3, MeCN 0 °C

MeO

Me N N Me

MeO

83% N Me

MeO

102

OMe

OMe

103

Br

Scheme 26 MeO

Ph

N SO2Ph

MeO

MeO

TTFA, MeCN BF3.OEt2 MeO

70%

Ph

N PhO2S

104

SO2Ph N

Ph

OMe

OMe

105 NO2 NO2 MeO

OMe

TTFA, MeCN BF3.OEt2

MeO

OMe

35% N COCF3

MeO

N H OMeHN

MeO H N

NO2 OMe

106

O2N

107

Scheme 27

N-phenylsulfonyl group is problematic. During the exploration of alter­ native N-protecting groups, it was found that the indole 106 was oxidized to the 7,7�; 2,7�-terindole 107 in 35% yield.

114

David StC Black and Naresh Kumar

HN Ph

hν dioxan

Ph N

OH

16%

Ph N H

108

109

Scheme 28

Photo-irradiation of the N-hydroxyindole 108 in dioxane gave a com­ plex mixture of products, of which six were isolated: one of these was the 3,3�-biindolyl 109, formed in 16% yield (98T5305) (Scheme 28). Electrochemical oxidation of indoles possibly leads to biindolyls in low yield. The oxidation of indole 36 in a phosphate buffer and using a pyrolytic graphite electrode gives a trimer, with the suggested reduced terindolyl structure 110 (but more likely to be the related 2,3-di(3-indo­ lyl)-2,3-dihydroindole) (98BB47). Similarly the 3-hydroxymethylindole 111 is oxidized to the 1,1�-biindolyl 112, whereas the comparable chemical oxidation using persulfate gives the simple 1,1-biindolyl 113 together with its hydroxylated analog 114 (01JCS(P2)618) (Scheme 29). It is also N

–e–

N

N H

N H

36

110 CHO OH N N

–e – N H 111

OHC

112

OH

OH

HO

OH S2O82–

N N

N H 111

HO

113

Scheme 29

N N

+

11%

HO

114

31%

115

Biindolyls

proposed, without evidence, that 1,2-dimethylindole is oxidized electro­ chemically to the 3,6�-biindolyl (91T737). The oxidation of 5,6-dihydroxyindoles has been extensively studied because of its relevance to the formation of melanin pigments, and has proven to be a source, albeit in very small yields, of a variety of biindolyls and more complex terindolyls and tetraindolyls (05AHC1). For example, chemical or enzymatic oxidation of 5,6-dihydroxyindole 115 gives initi­ ally the 2,4�-biindolyl 116, the 2,7�-biindolyl 117, and the 2,2�-biindolyl 118. Dimers 116 and 117 are subsequently converted into the terindolyls and tetraindolyls 119—121 and 122—124, respectively (07OL1411, 07JOC9225) (Scheme 30). The related 2-carboxylic acid 125 undergoes autoxidation with oxygen and copper (II) sulfate to form a 4,4�-dimer, which after methylation and acetylation gives the 4,4�-biindolyl 126, which can be isolated in 5% yield (87TL467) (Scheme 31). The more reactive 5,6-dihydroxy-2-methylindole

HO HO

+ [O] metal cation

HO

N H

HO

NH

N H

HO

H N

HO

N H

OH

N H

HO 115

HN

117 +

HO HO

OH

HO

OH

116

OH 118

2,4′; 2,4′; 2,4′-tetraindolyl + 2,4′; 2,4′-terindolyl + 2,4′; 2,7′-terindolyl

116

119

120

121

2,7′; 2,3′; 2,7′-tetraindolyl + 7,2′; 3,3′; 2,7′-tetraindolyl + 2,7′; 4,4′; 7,2′-tetraindolyl

117

122

123

5%

124

3%

4%

Scheme 30

HO CO2H N H

HO

5%

H N

AcO

1. [O], CuSO4 2. MeOH 3. Ac2O

CO2Me AcO OAc MeO2C N H

125

OAc 126

Scheme 31

116

David StC Black and Naresh Kumar

gives 3,3�-, 3,4�-, 3,7�-, and 7,7�-biindolyls, as well as the 3,3�; 7,2�-terindolyl, again isolated as the acetates in very low yields (93T9143).

3. REACTIONS In general, the reactions of biindolyls reflect the reactivity of simple indoles and are therefore not of any particular interest. Therefore, this section will only consider some interesting cyclization reactions. The most important of these are encountered in syntheses of the biologi­ cally active indolocarbazoles. For example, the Diels—Alder addition of maleimides to 2,2�-biindolyls has been investigated but generally gives low yields of the desired indolocarbazoles, with Michael addition products being preferred. However, the Michael products can very effectively be cyclized to the indolocarbazoles. For example, when the 2,2�-biindolyl 127 is heated with N-benzyloxymaleimide at 105�C for 8 days, the indolocarbazole 128 is produced in 22% yield (85TL4015). In contrast, the Michael adduct 129 undergoes photo-cyclization to the indolocarbazole 130 in 90% yield (93TL5329, 95T12797) (Scheme 32). Similar photo-cyclization of a related pyrrolone is also effective (03TL2577). A 36% yield of indolocarbazole 95 is obtained from the 2,2�-biindolyl dithiete 131 (99TL3795). Reaction of the dithiete 131 with dibromomalei­ mide and tri-n-butylphosphine gives a 47% yield of the eight-membered ring 132, which undergoes a sulfur contraction reaction to yield 95 in 58% (00TL9835) (Scheme 33).

OAc

H N

N H

Cl

Cl O

CH2OBn N O

105 °C, 5 days 22%

H N

O

Cl

N H

127

O

Me N

O

N H 128 Me

N

O

O

O hν

N Me

N Me

90%

129

N Me 130

Scheme 32

N Me

Cl

117

Biindolyls

O

S S

N H

H N

N H

131 O

O

O

36%

N H

H N

O

N H 95

n-Bu3P

H N

Br

O Br

H N

O S

O

150 °C, 24 h 58%

S

47% NH HN 132

Scheme 33

Cycloaddition reactions are easier to control with 3,3�-biindolyls than with 2,2�-biindolyls. Thus 3,3�-biindolyl 72 forms indolocarbazoles in mod­ erate to good yields on heating under different conditions with dimethyl acetylenedicarboxylate, N-substituted maleimides, or maleic anhydride. The reaction of 72 with N-benzylmaleimide is illustrated to give indolo­ carbazole 133 (98JCS(P1)2009) (Scheme 34). A similar cycloaddition of N­ benzylmaleimide with the 2,3�-biindolyl 51 gave the indolocarbazole 134, which could also be formed in a stepwise fashion by reaction of 51 with dimethyl acetylenedicarboxylate followed by benzylamine. However, the parent indolocarbazole 136 could be formed by reaction of 51 with dimethylaminoacetaldehyde diethyl acetal in acetic acid or by cyclization of the 3-nitrovinyl derivative 135 of 51 in boiling xylene (99T2363, 99T2371). The indolocarbazoles 138 and 139 can be formed via a palladiumcatalyzed benzannulation of the 3-iodo-2,2�-biindolyl 137 with ethyl phe­ nylpropiolate in 59% and 29% yields, respectively (97TL7661, 01T5199) (Scheme 35). Chromium carbene complexes of 2,2�-biindolyls can be converted to indolocarbazoles by heating with t-butylisocyanide or photo-irradiation with carbon monoxide: for example, complex 140 gives the amine 141 and the phenol 142 in 89% and 51% yields, respectively (01T5199) (Scheme 36). New six-membered rings can be formed in a variety of simple cycliza­ tion reactions. For example, the 2,2�-biindolyl 143 can be cyclized to 144 by treatment with base, on the way to a synthesis of calothrixin B (07TL231) (Scheme 37). The 2,3�-biindolyl lactam 146 can be formed by the

118

David StC Black and Naresh Kumar

H N O

O N CH2Ph

HN

Ph2O, 190 °C

N H

NH

O

O N CH2Ph

69% 133

72 O

NH N

H

O

CH2Ph N O

O

N CH2Ph

NH

HOAc N H 51

134 (EtO)2CHCH2NMe2 HOAc reflux

1. Me2NCHO POCl3 2. MeNO2 NH4OAc

86% 91% NO2 NH

xylene reflux

NH

N H

81%

N H

136

135

Scheme 34

EtO2C

I

EtO2C

Ph

Ph

CO2Et

Ph +

N Ts

N

Ms 137

Pd(PPh3)4

Tl2CO3

toluene

N Ts

N Ms 138

N Ms

N Ts 59%

139

29%

Scheme 35

nitrosation and reduction of the 2,3�-biindolyl ester 145 (04TL7273). A lactam can also be formed when the Suzuki—Miyaura coupling reaction generates a 3,7�-biindolyl in which an indole NH can attack an appropri­ ately located ester function (08JOC9177). Attempted formylation of the 7,7�-biindolyl 66 also leads to cyclization onto an indole nitrogen atom (96T7003).

119

Biindolyls

(OC)5Cr

MeO

NHt-Bu

OMe t-BuNC

N Me

89%

N Me

N Me

140

N Me 141

(OC)5Cr

MeO OMe

OH

CO, hν toluene 51%

N N Me Me 140

N Me

N Me 142

Scheme 36

O

CHCl2

H

N

N H

Cl OH

N H

N

NH3

AcO 143

144 O

MeO2C

HN

NH

1. NaNO2, HOAc 2. Zn, HOAc

N H

57% MeO

O

NH N H

OMe

OMe MeO 146

145

Scheme 37

Examples of seven-membered ring formation have been reported with 2,2�-biindolyls. When the 2,2�-biindolyl 2 is heated with 4-dimethylamino-1,1,1-trifluoro-3-buten-2-one and triflic anhydride, 147 is formed in 86% yield (03CHC776) (Scheme 38). Also the cyanoacetyl 148 reacts with 4-chlorobenzaldehyde to give the cyclized 149 (07JOC5886). An interesting product 150 containing an azepine ring can also be formed by the reaction of 148 with sodium nitrite in acetic acid (Scheme 38). An eight-membered tetrasulfide 99 is formed in the reaction of 3,3�­ biindolyl 72 with sulfur, but the related reaction with 2,2�-biindolyl 2 yields a dimeric structure 151 (02EJOC1392, 02JCS(P1)330) (Scheme 39).

120

David StC Black and Naresh Kumar

H N N H

F3C

COCF3

Me2N

(CF3SO2)O

N H

86%

2

Cl

O CHO

Cl

H N

N H

N H

72% 148

N H 149 CN

CN

O

147

CN

CN

O

N

O N

H N

O

NaNO2, HOAc

N H

N H

64% 148

N H 150

Scheme 38 H

N

S8, DMF HN

NH

59% N H

S

S 72

H N N H

99

S S H N

H N

S8, xylene

S

S

76%

S

S

N H 2

N H 151

Scheme 39

4. CONCLUSION The great majority of the chemistry of biindolyls has focused on those with 2,2�-, 2,3�-, and 3,3�-linkages. There is therefore extensive scope to explore completely new biindolyl systems, and this area of research is likely to be very rewarding in the future.

Biindolyls

121

REFERENCES 12CB1128 14LA58 60JA2739 60TL13 61JCS940 62JOC507 64JOC2030 72JCS(P1)418 78KGS217

80T1439 80T1445 80TL1883 81H1441 82JCS(CC)977 83AJC2407 83JCS(CC)1074 84JCS(CC)441 84JCS(P1)2305

84JHC623 84T3251 85JCS(CC)1174 85TL4015 86T5019 87TL467 88CB2259 89JCS(CC)111 89JCSR277 90KGS343 91T737 92KGS1336

93SL246 93T9143

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93TL5329 93TL8361 94AJC1741

94S25 94T10497 94TL793 94TL5555 95SL859 95T5631 95T12797 95TL7841 96T4697 96T7003 96T8099 96TA285 96TL5207 97H1647 97TL7661 98ANH85 98BB47 98JCSP(1)1619 98JCS(P1)2009 98SC1239 98T5305 98TL7677 99H1233 99T2363 99T2371 99TL3795 99TL6653 99TL7615 00TL9835

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Biindolyls

01JCS(P2)618 01T5199 02EJOC1392

02JCS(P1)330 03CHC776 03OL3721 03TL2577 04H483 04S610 04T3695 04TL7273 05AHC1 05T853 05T10490 06TL6385 07JOC5886 07JOC9225 07OL1411 07TL231 07TL7399 08JOC9177 08OBC2481 08T7787 10H1267

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CHAPTER

4 The Annulation of 2-Imidazolines Raymond C F Jones

Contents

1. Introduction 2. Polar Annulation Strategy 3. Imidazolines as Double Nucleophiles 3.1 Synthesis of substrates 3.2 Lateral metallation at C-2(a) 3.3 Enamine reactivity of the enamino ester 4. Annulations of the Enamino Ester/Ketene Aminal 4.1 Dihaloalkane electrophiles 4.2 a,b-Unsaturated aldehyde and ketone electrophiles 4.3 a,b-Unsaturated acid derivatives as electrophiles 4.4 1,3-Dicarbonyl compounds as electrophiles 5. Annulations of N-Unsubstituted 2-Imidazolines 5.1 a,b-Unsaturated aldehyde and ketone electrophiles 5.2 a,b-Unsaturated ester electrophiles 5.3 b-Keto esters as electrophiles 5.4 Diethyl acetylenedicarboxylate as electrophile 6. Imidazolines as Sources of 1,3-Dipoles 6.1 Synthesis of substrates 7. Azomethine Ylides by AlkylationDeprotonation 8. Azomethine Ylides by Carbene Insertion in a Catalytic

Cycle 9. Azomethine Ylides by Conjugate Addition-Proton

Transfer 9.1 Annulation via the conjugate addition route with

singly activated alkenes and with alkynes 10. Annulations Using Chiral Imidazolines 10.1 Synthesis of substrates

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Department of Chemistry, Loughborough University, Loughborough, Leicestershire LE11 3TU, UK This account is largely a personal view of an area of the author‘s own research over three decades. It does not set out to be comprehensive, so the author apologizes in advance for any lack of acknowledgment of related work. Advances in Heterocyclic Chemistry, Volume 101 ISSN 0065-2725, DOI 10.1016/S0065-2725(10)01004-4

 2010 Elsevier Inc. All rights reserved

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11. Optically Active Piperidines via Enamino Ester Annulation 12. Dipolar Cycloaddition of Optically Active Imidazolinium Ylides 13. Chiral Imidazoline Nitrones in Cycloadditions 14. Summary References

151 152 156 158 159

1. INTRODUCTION The 2-imidazoline (4,5-dihydroimidazole) heterocyclic ring system (1) is of interest for a number of reasons. The first is medicinal. There are several imidazoline-based molecules in service in the clinic and several others with significant activity at adrenoreceptors (06MI1). One classic example is cloni­ dine (2), which is used as an antihypertensive agent (09MI617), and (as any Internet search will quickly reveal) has found new uses, including treatment of some types of neuropathic pain, opioid detoxification, sleep hyperhidro­ sis, anesthetic, insomnia relief of menopausal symptoms, and (in conjunction with stimulants) treatment of attention-deficit hyperactivity disorder. Cloni­ dine can be used in the treatment of Tourette syndrome and as a premedica­ tion before surgery. Clonidine acts an a2-adrenoreceptor agonist, with selectivity for presynaptic receptors. It decreases cardiac output and periph­ eral vascular resistance, lowering blood pressure. Other related imidazolines are oxymetazoline (3), a selective a1-agonist and partial a2-agonist used as a topical decongestant, and phentolamine (4), an a2-antagonist used for the control of hypertensive emergencies. A family of imidazoline receptors has been defined, known as I1—I3 (06MI217). I3 receptors mediate the sympatho­ inhibitory actions of imidazolines to lower blood pressure.

Another stimulus for interest in imidazolines is their relationship to Nature‘s carbon-transfer coenzymes, the family based on tetrahydrofolic acid (FH4) (5) (04MI1112) (10MI3816). N5,N10-Methenyltetrahydrofolate (6) is an intermediate in the transfer of a C-1-unit (the imidazoline C-2 carbon, indicated by an asterisk) at the formate oxidation level, and is an imidazo­ linium salt. N10- and N5-Formyl-FH4, along with N5-formimino-FH4, are

The Annulation of 2-Imidazolines

127

also responsible for this transfer. Redox processes connect N5,N10-methe­ nyl-FH4 to N5,N10-methylene-FH4 (7), the tetrahydroimidazole reduction product, which transfers C-1 units at the formaldehyde oxidation level, and N5-methyl-FH4 (8), which operates at the methanol oxidation level. In addition, ylides potentially formed from 2-unsubstituted imidazolines can be regarded as mimics of the thiamine coenzyme thiazole moiety (04MI2176, 05MI1132, 05MI1209, 10MI1566, 10MI2688) and indeed we have exploited the potential of such ylides (90TL1767, 90TL1771).

This background provided the motivation to explore imidazoline chemistry, both to produce novel molecules of biological potential and to exemplify the relationship of imidazoline chemistry to coenzymemediated chemistry. This chapter will focus in particular on the annulation of imidazolines to produce novel heterocyclic molecules. Our objectives were to use imidazolines in synthesis, and as templates for new rings; to make aza-analogues of biologically significant systems; to develop new routes to 5- and 6-membered rings, and bicyclics; and to contribute to the asymmetric synthesis of heterocycles. This chapter will deal with the chemistry in the achiral molecules first and then show where and how it has been applied to chiral and optically active situations.

2. POLAR ANNULATION STRATEGY The general strategy for our initial studies was based on the notion that imidazolines substituted with alkyl groups at C-2 should display two sites of nucleophilic reactivity, namely, at N-1 and at C-2(a). The lateral metallation was not known at the start of our endeavors, although related chemistry of 2-oxazolines had been reported; for recent reviews see (05JOC6137, 08CHEC-III(4)510). Such double nucleophilicity would lend itself to annulation via reaction with a range of doubly electrophilic species, to generate varying sizes of fused ring (Scheme 1). Further on in our studies we also postulated the conversion of imida­ zolines into 1,3-dipoles by suitable functionalization at N-1, and that this would allow dipolar cycloaddition as an annulation strategy for

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Scheme 1

imidazolines with five-membered rings. We have realized both of these approaches and will describe them herein.

3. IMIDAZOLINES AS DOUBLE NUCLEOPHILES First, it is necessary to introduce the enabling synthetic methodology underpinning the double nucleophile—double electrophile annulation. Our first steps were to generate suitable imidazoline substrates to estab­ lish the C-2(a) nucleophilic reactivity.

3.1 Synthesis of substrates Attempts to demonstrate C-2(a)-anion reactivity by double deprotona­ tion of commercially available 2-methyl-2-imidazoline provided mixed results, and indicated that extra stabilization of the lateral position, for example, by the phenyl group in 2-benzyl-2-imidazoline, was necessary to support a dimetallated species. This was in line with the findings of others (98JOC8107, 98TL8979). It was therefore necessary to seek suitable N-substituted 2-methyl-2-imidazolines. Much of our early work used N-benzyl derivatives, as a group poten­ tially removable from N-1. Thus we prepared 1-benzyl-2-methylimidazoline (9) by straightforward reaction of N-benzyl-1,2-diaminoethane (whose pre­ paration was already reported) with a C-2 unit at the carboxylic oxidation level (Scheme 2) (81TL261, 86JP1205). This latter was the imidate prepared

Scheme 2

The Annulation of 2-Imidazolines

129

from acetonitrile and ethanol in the presence of hydrogen chloride. In later studies discussed below, we used N-tert-butyloxycarbonyl-2-methyl-2-imi­ dazoline (10), prepared simply from commercial 2-methyl-2-imidazoline (trivially known as lysidine) and di-tert-butyl dicarbonate (Equation (1)) (00T2061).

We also prepared a possible alternative substrate for the C-2(a) nucleophilic reactivity, 1-benzyl-2-(ethoxycarbonylmethylene)-1,2,3,4­ tetrahydroimidazole (11), which may be regarded as an enamino ester or a ketene aminal. This could display the desired nucleophilic poten­ tial through its enamine functionality, and the alkoxycarbonyl group regarded as an activating group. This group should be removable, by analogy with acetoacetate/malonate chemistry. The enamino ester was accessed from 1-benzyl-2-imidazoline prepared as above, by metalla­ tion and C-acylation with diethyl carbonate, or much more conveni­ ently directly from N-benzyl-1,2-diaminoethane and an imidate prepared from ethyl cyanoacetate and ethanol in the presence of hydro­ gen chloride (Scheme 2) (84JP12599). Much of our annulation work was performed on this enamino ester as a stable substrate, as will become clear below.

3.2 Lateral metallation at C-2(a) Lateral metallation of 2-methyl-2-imidazolines was demonstrated by C-2(a)-deprotonation of the N-benzyl compound 9 using n-butyl­ lithium (n-BuLi) at low temperature and alkylation with alkyl halides (Scheme 3) to afford derivatives 12 (81TL261, 86JP1205). A second deprotonation—alkylation reaction could also be achieved, although a third such successive step was not possible. The a-branched 2-alkyl-2­ imidazolines 13 could be hydrolytically cleaved under acidic conditions to realize the potential of the 2-imidazoline system in C-2 transfer: here the 2-methyl-2-imidazoline functions as an ethanoate enolate equivalent. The C-2(a) nucleophilic property was combined with N-1 nucleo­ philic potential in two sequences, illustrated by the assembly of some imidazolines that were made as potential aza-analogues of prostaglan­ dins (Scheme 4) (90JP1373). In one sequence, C-alkylation was per­ formed first on 1-benzyl-2-methyl-2-imidazoline (9), and the N-benzyl

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Raymond C.F. Jones

Scheme 3

Scheme 4

group was removed from the C-alkylated product by dissolving metal reduction. The liberated NH function was subsequently alkylated using n-BuLi at 0C and an alkyl halide, which in this case also carried a masked carboxylic acid function that was revealed in a final step. The alternative sequence used commercial 2-methyl-2-imidazoline, which was first N-alkylated at N-1 with the same w-functionalized alkyl halide introduced in the first sequence (n-BuLi at 20C) and then reacted at C-2(a) as described above to produce the same doubly alkylated material 14, from which the masked carboxylic acid was revealed as its methyl ester. In order to avoid the dissolving metal step to remove the N-1 benzyl substituent, we developed an alternative protocol for C-alkylation to give N-1 unsubstituted imidazolines. In this we employed 2-methyl-N-tert­ butyloxycarbonyl (Boc) imidazoline (10) (Scheme 5). Deprotona­ tion—alkylation was now accomplished using sec-BuLi-TMEDA followed by an alkyl halide, and the Boc group was simply removed by trifluoroacetic acid (TFA) treatment (00T2061).

The Annulation of 2-Imidazolines

131

Scheme 5

The C-2(a) metallation reactivity has also been demonstrated on ring-fused imidazolines: 1-benzyl-2-methyl-3a,4,7,7a-tetrahydro-1H­ benzimidazole (90JP1373), 3-methyl-1,5,6,10b-tetrahydroimidazo[5,1-a] isoquinoline, and 1-methyl-3,3a,4,5-tetrahydroimidazo[1,5-a]isoquino­ line (90JP1385), the latter designed as mimics of N5,N10-methenyltetra­ hydrofolate (6). We have selected to illustrate the nucleophilic reactivity of C-2(a) by alkylation reactions; in addition, the nucleophilic a-lithioalkyl imidazo­ lines also react with carbonyl electrophiles in addition and condensation reactions (88TL5001, 97T1111), some of which will be relevant to the annulation chemistry discussed below.

3.3 Enamine reactivity of the enamino ester 11 Our alternative substrate as a C-2(a) nucleophile, the enamino ester 11, was also validated by deprotonation—alkylation (Scheme 6). Dou­ ble alkylation was also successful, although two successive alkylations to produce unsymmetrical dialkylation, was not (91JP1953, 97T11781). Acidic hydrolysis accompanied by the expected decarboxylation was shown to remove the ethoxycarbonyl group and confirmed the enam­ ino ester as an activated synthetic equivalent of the C-2(a) anion.

Scheme 6

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Raymond C.F. Jones

Again, as will become clear from our annulation studies described later, the enamino ester 11 also reacts, as expected, with carbonylbased electrophiles.

4. ANNULATIONS OF THE ENAMINO ESTER/KETENE AMINAL As was stated earlier, much of our annulation work was performed on the enamino ester/ketene aminal 11 as a stable activated substrate, and using a range of bis-electrophiles across the spread of potential oxidation levels.

4.1 Dihaloalkane electrophiles With this enabling chemistry in hand, we were able to embark on annulation studies. Our first forays into this area used the enamino ester 11 and dihaloalkanes. When using a 1,3-dihaloalkane, alkylation under basic conditions was observed at both N-1 and C-2(a), leading to imidazo[1,2-a]pyridines (Scheme 7) (91JP1953, 97T11781). The initial alkylation was deduced to be at C-2(a) from the product regiochemis­ try, which showed the presumably more reactive primary 1-bromo function to become attached at the enamino ester carbon, with the secondary 3-bromo center providing the N-alkylation. This preference for C-alkylation manifested itself again when using 1,4-dibromobutane or 1,5-dibromopentane, when double C-alkylation was observed to give the 1,1-disubstituted cyclopentane and cyclohexane derivatives, rather than ring-fused annulation products. 1,2-Dibromoethane resulted in the recovery of starting material under the same reaction conditions.

Scheme 7

The Annulation of 2-Imidazolines

133

4.2 a,b-Unsaturated aldehyde and ketone electrophiles Continuing with the enamino ester 11 as substrate, and moving to a bis-electrophile one oxidation level higher than a dihaloalkane, we explored the reactions with conjugated aldehydes (89TL5361, 98T6191). In this case, we found once again the tendency for C-nucleo­ philicity to lead the annulation. Thus, conjugate C-addition of the enamino ester onto the a,b-unsaturated aldehydes was found, with the presumed initial conjugate adduct undergoing tautomerization to allow N-1(H) cyclization onto the aldehyde group to form an enamine (Scheme 8). The resulting imidazo[1,2-a]pyridines can be viewed as unsymmetrical 1,4-dihydropyridines related to the calcium channel block­ ers such as Nifedipine. The apparently small change to using a,b-unsaturated ketones as the bis-electrophiles led to a different outcome. The initial conjugate C-addi­ tion products could be isolated and resisted the cyclization step (89TL5361, 98T6191). Instead, when they were reduced by sodium bor­ ohydride, these adducts underwent a cascade of steps to afford low yields of N(1)-substituted 3-alkoxycarbonyl piperidines or tetrahydro­ pyridines 18 (89TL5365). This is believed to occur via an initial annulation step (Scheme 9). Cyclization of N-1 onto the ketone carbonyl leads to an iminium salt 15, which can be captured by hydride reduction. Water

Scheme 8

Scheme 9

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Raymond C.F. Jones

Scheme 10

elimination leads to a second iminium salt 16, which is also reduced by hydride. The aminal produced can ring-open to a third iminium ion 17, from which hydride reduction or simple proton loss leads to the observed piperidine or tetrahydropyridine products 18. This sequence, although mechanistically interesting, did not occur in high yield. If the reducing system applied to the conjugate C-adducts was switched to hydrogen and Adams catalyst, or borane-THF, then an annu­ lation—reduction cascade whose mechanism is not certain but must be related to the hydride-mediated sequence described above, leads to the same N(1)-substituted 3-alkoxycarbonyltetrahydropyridines 19 as with NaBH4 (Scheme 10) (89TL5365). Acid treatment completes hydrolysis—decarboxylation, with cyclization of the intermediate imi­ nium ion to give imidazo[1,2-a]pyridines 20. Hydrolysis—decarboxylation of the initial conjugate addition products before the reductive sequence leads directly to the same imidazopyridines. Some other modifications of the tetrahydropyridines 19 have been achieved. In all of these [3þ3] annulations of the enamino ester 11 to imidazo­ pyridines, the enamino ester is functioning as an acetaldehyde enamine equivalent.

4.3 a,b-Unsaturated acid derivatives as electrophiles The next set of annulations employed bis-electrophiles one step higher in oxidation level, unsaturated acid derivatives. Treatment of the enamino ester 11 with the a,b-unsaturated ester ethyl propenoate pro­ ceeded via a (presumed) imidazo[1,2-a]pyridin-5-one 21 (R = H) to afford an isolated cyclol 22 (R = H) by hydration when chromato­ graphed on silica (Scheme 11) (88TL5005, 98T6191). Based on the find­ ings with other bis-electrophiles discussed above, we assume this

The Annulation of 2-Imidazolines

135

Scheme 11

reaction proceeds via conjugate C-addition followed by N-1 acylation. This sequence is supported by the isolation of the conjugate C-addition product 23 from reaction of the enamino ester with ethyl propynoate. An aza-ene proposal (24) has been made by others for such conjugate additions (93JP11085, 99JP12087).

In an attempt to switch the sequence of steps, more activated acid derivatives were selected as electrophiles, and propenoyl chloride gave the same imidazopyridin-5-one 21 (R = H). A more convenient protocol was found based on in situ preparation of a,b-unsaturated acyl imidazolides 25: thus an a,b-unsaturated acid was pretreated with 1,10 -carbonyldiimidazole before addition of the enamino ester (88TL5005, 98T6191). A simple partition between chloroform and aqueous sodium hydrogen carbonate led to isolation of the imidazo­ pyridin-5-ones 21 in good yield, now presumably via N-acylation followed by conjugate C-addition (Scheme 11). In some cases they were converted into the cyclols 22 if chromatographed on silica,

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Raymond C.F. Jones

although the products from phenylpropenoic acid and propynoic acid proved stable toward such chromatography.

4.4 1,3-Dicarbonyl compounds as electrophiles 1,3-Dicarbonyl compounds would be the next rung up the oxidation ladder. However, attempts to react the enamino ester 11 with 1,3-dike­ tones were unsuccessful, with starting materials recovered. Using 1,3­ diesters as the double electrophile gave no reaction with the enamino ester. On the other hand b-keto esters afforded excellent yields of imida­ zopyridinones: ethyl acetoacetate gave mixtures of imidazopyridin-5-one 26 (R = Et) as major product and the corresponding 7-one 27 (R = Et) as minor product, whereas ethyl benzoylacetate afforded solely the imida­ zopyridin-5-one 26 (R = Ph) (Scheme 12) (88TL5005, 98T6191). These products arise from competing acylation at N-3 or C-2(a). Our earlier findings suggest that conjugate C-addition to a,b-unsaturated systems is the preferred reaction of the enamino ester. We therefore rationalize the findings with 1,3-dicarbonyl compounds by proposing a similar pathway of initial conjugate C-addition to the enol of the 1,3-dicarbonyl compound, to give intermediates 28. This addition, illustrated in 29, accounts for the preferred regiochemistry of annulation using b-keto esters (98T6191); the lack of reaction with 1,3-diesters may be attributable to their much lower enol content (e.g., diethyl malonate 7.7  103% vs. ethyl acetoacetate 8.0% in pure compound). 1,3-Diketones have much higher enol content (pentane-2,4-dione 76.4% neat) and so are proposed to undergo ready conjugate C-addition, but that the primary adduct will resist cyclocondensation (as was observed with a,b-unsatu­ rated ketones (Scheme 9) (89TL5361)). Our experience with 2-(2-hydro­ xyalkyl)-2-imidazolines, formed from adding 1-benzyl-2-lithiomethyl-2­ imidazoline to ketones, when it was found that this addition was readily reversible (88TL5001, 97T1111), suggests that the primary adducts from 1,3­ diketones will undergo similar retro-aldol fragmentation (Equation (2)) under the reaction conditions (toluene at reflux, with or without toluene4-sulfonic acid, or THF—NaH at reflux).

Scheme 12

The Annulation of 2-Imidazolines

137

Scheme 13

As a representative 1,2-bis-electrophile, diethyl oxalate was found to react with the enamino ester 11 under acidic conditions (neutral and basic conditions having produced no reaction) to afford a dioxo­ pyrrolo[1,2-a]imidazole 30 (Scheme 13) (98T6191). Interrupting the reaction before completion indicated an N-acylated intermediate 31; arguments about conjugate addition clearly cannot be applied in this case. Taken with the unsuccessful 1,2-dibromoethane result shown earlier, it can be seen that there clearly remains scope for further 1,2-bis-electrophiles at various oxidation levels to be investigated with the enamino ester.

5. ANNULATIONS OF N-UNSUBSTITUTED 2-IMIDAZOLINES The range of C-2(a)-unactivated, N-unsubstituted 2-alkyl-2-imidazolines made available by our deprotonation—alkylation—deprotection protocol from N-tert-butyloxycarbonyl-2-methyl-2-imidazoline (00T2061), opened up further avenues for annulation, and indeed produced some results

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Raymond C.F. Jones

distinct from those observed for the enamino ester, detailed in the preceding sections.

5.1 a,b-Unsaturated aldehyde and ketone electrophiles Heating a variety of 2-alkyl-2-imidazolines 32 with a set of a,b-unsatu­ rated aldehydes & ketones under conditions of water removal, led to a range of tetrahydroimidazo[1,2-a]pyridines 33 (Scheme 14) (00JP12331); there was no evidence of enamine formation at N-1. The regiochemistry of the annulation products, as confirmed by NMR studies, is consistent with conjugate N-addition onto the enals and enones, followed by an enamine—aldol reaction of the C-2(a) carbon center as nucleophile with the former enal or enone carbonyl group. Amongst supporting evidence for this pathway were the following observations: isolation of the pre-dehydration intermediate 34 (R1 = CH2CH = CH2; R2 = Me; R3 = H) (27%) from reaction of the 2-(prop-2-enyl)-2-imidazoline with but-2-enal at 20C (CH2Cl2, MgSO4); isolation of the tautomeric alcohols 34 and 35 (R1 = Ph; R2 = H; R3 = Me) as a 1:1 mixture (42%), along with the corre­ sponding dehydration product 33 (21%) from reaction of 2-benzyl-2­ imidazoline and but-3-en-2-one under the same conditions; and isolation of the enediamine alcohol 35 (R1 = Ph; R2 = Me; R3 = H) (37%) from reac­ tion of the 2-benzyl-2-imidazoline and but-2-enal under the reflux condi­ tions but in more dilute solution. It is possible that the conjugation in alcohols 35 (R1 = Ph) favors the enamine form of the aldol product and inhibits dehydration. When 2-(prop-2-enyl) or 2-benzyl-2-imidazolines were treated at 20C in MeOH with but-3-yn-2-one, the E-enamines 36 were isolated, again the products of conjugate N-addition. The control of regiochemistry of these annulations by conjugate N-addition is thus in direct contrast to the situation with the activated imidazoline enamino ester, where conjugate C-addition is dominant

Scheme 14

The Annulation of 2-Imidazolines

139

(98T6191). This led us to investigate whether this reversal would extend to other bis-electrophiles.

5.2 a,b-Unsaturated ester electrophiles Treatment of 2-benzyl-2-imidazoline (32; R1 = Ph) with methyl propeno­ ate afforded the conjugate N-adduct 37, in support of the preference for this first step with unactivated NH-imidazolines (Scheme 15). Annulation could be completed by C-2(a) metallation and condensation onto the ester function (00JP12331). The conjugate N-adducts were also isolated from reaction of several 2-alkyl-2-imidazolines 32 with methyl propyno­ ate, as separable Z:E geometric isomer mixtures 38.

5.3 b-Keto esters as electrophiles Heating a set of the 2-alkyl-2-imidazolines 32 with ethyl acetoacetate, ethyl benzoylacetate, and ethyl 2-oxocyclohexanecarboxylate afforded the corresponding imidazopyridin-5-one 39 and the imidazoisoquinolin­ 5-one 40 (Scheme 16) (00JP12331). The regiochemistry is based on NOE studies and secured by an X-ray crystal structure of the imidazoisoquino­ linone 40 (R1 = Ph) formed from 2-benzyl-2-imidazoline. Although initial reaction of the imidazoline N-1 at the keto-carbon (either through direct 1,2-addition or through conjugate addition to the enol form) leading to the enamine may be the kinetic product based on the findings above, forma­ tion of the more stable amide linkage appears to control the regiochemistry

Scheme 15

Scheme 16

140

Raymond C.F. Jones

under these reaction conditions. This observed regiochemistry is in con­ trast to the reported reaction of 2-benzyl-2-imidazoline and b-keto esters to afford products assigned as the regioisomeric imidazopyridin-7-ones 41 (78JHC1021), so that we could conclude the reported structures were misassigned. Indeed our data match those for the reported compounds.

5.4 Diethyl acetylenedicarboxylate as electrophile The 2-alkyl-2-imidazolines 32 react under mild conditions with diethyl acetylenedicarboxylate to give (E)-conjugate adducts 42 and Z-tetrahy­ dropyrrolo[1,2-a]imidazol-6-ones 43 (Scheme 17) (00JP12331). Base treatment of the adducts led to the (Z)-pyrroloimidazoles and their (E)-isomers, and prolonged reaction led to mixtures of the annulation products. The annulation thus once again proceeds via initial conjugate N-addition of the 2-alkyl-2-imidazolines, but the acetylene dicarboxylates function as 1,2- rather than 1,3-bis-electrophiles and the sequence con­ cludes with C-2(a)-acylation rather than with conjugate C-addition and imidazopyridine formation. This reactivity preference is in accord with an X-ray structure of one of the intermediate conjugate N-adducts 42 (from 2-(2-phenylbenzyl)-2-imidazoline), which shows in the solid state that the a-ester group is situated close to the C-2(a) carbon whereas the b-ester is part of a planar conjugated enamino ester system and is deactivated.

6. IMIDAZOLINES AS SOURCES OF 1,3-DIPOLES The general strategy here was to convert 2-unsubstituted 2-imidazolines into 1,3-dipoles, by appropriate derivatization at N-1 to form a quatern­ ary nitrogen atom carrying a negatively charged atom X, and to react these with dipolarophiles to complete an annulation with a new fivemembered ring (Scheme 18). We have realized this with X as carbon fragments, generating azomethine ylides (imidazolinium ylides) and with X as oxygen to create nitrones (imidazolinium N-oxides). Efforts to

Scheme 17

The Annulation of 2-Imidazolines

141

Scheme 18

validate this approach with 2-substituted 2-imidazolines were not fruitful so will not be discussed further here.

6.1 Synthesis of substrates The 2-unsubstituted imidazolines 44–47 required for azomethine ylide formation were very easily prepared by reaction of N-benzyl-1,2-diami­ noethane (prepared as Scheme 2) or the commercial N-methyl, N-butyl, and N-phenyl diamines, respectively, with this time a C-1 unit at the carboxylic oxidation level, such as triethyl orthoformate or dimethylfor­ mamide dimethyl acetal (Scheme 19) (90TL2333, 98JP12061, 07MI1, 08MI1).

7. AZOMETHINE YLIDES BY ALKYLATION�DEPROTONATION One classic route to azomethine ylides involves N-alkylation of an imine and deprotonation of an sp3 carbon atom attached to the iminium carbon. Thus the first approach to imidazolinium ylides involved alkylation of 1-benzyl-2­ imidazoline (44) with an active halide (bromoacetate esters, chloroacetoni­ trile) in diethyl ether, removal of solvent from the deposited quaternary salt 48, replacement of the solvent by THF at reflux containing an excess of the dipolarophile, and then slow addition of 1,8-diazabicycloundec-7-ene (DBU) as base (90TL2333) (98JP12061). Other base systems (e.g., n-BuLi, Et3N, Hu¨nig‘s base, some phosphazene bases) were unsuccessful. This formed the assumed dipole 49 in low standing concentration, which under­ went cycloaddition with the dipolarophile. Suitable dipolarophiles were

Scheme 19

142

Raymond C.F. Jones

Scheme 20

electron-deficient alkenes, such as 2-methylpropenoate esters. In this way, new pyrrolo[1,2-a]imidazoles 50 were formed in diastereoselective fashion (Scheme 20). We subsequently streamlined this procedure to a one-step onepot protocol by adding, in one portion, the alkylating agent and dipolaro­ phile to the 2-imidazoline in THF at reflux, followed by slow dropwise addition of DBU to the mixture (93JP12391, 98JP12061). This produced effective reaction, even in cases where the alkylation reaction itself was shown to be slow. Dipole formation must therefore occur before alkylation is complete, and this presumably reduces the possibility of intervention of the hydrolytic sensitivity of the imidazolinium quaternary salts, or other side reactions. The product regiochemistry observed, with the dipolarophile-activat­ ing group located at C-7 of the pyrroloimidazole cycloadducts, is as pre­ dicted for a stabilized azomethine ylide with an electron-deficient dipolarophile, that is, Sustmann type 1 with HOMO-dipole/LUMO-dipo­ larophile orbital control (71TL2717). The major (sometimes exclusive) diastereomer of the cycloadducts was as shown in Scheme 20, as secured by extensive NOE studies. Its formation could be rationalized by a transi­ tion state 51 involving an anti-dipole (anti referring to the methine-H at the formally negative dipole terminus, and the C-2(H) of the 2-imidazoline) and endo approach of dipolarophile to dipole, that is, the activating group on the alkene dipolarophile lying under the ring of the imidazolinium dipole. The anti-dipole has been postulated by other groups to be favored, e.g., (90T6449, 94T895), and H-bonding between the imidazoline C-2(H) and the dipole-activating carbonyl group can be invoked. This model has served well for dipolar cycloadditions in our work. In some cases a minor amount of the exo diastereomer (i.e., the C-7 epimer) was observed.

The Annulation of 2-Imidazolines

143

Scheme 21

On standing or after chromatography using basic eluents, the cycloadducts underwent partial epimerization at the bridgehead car­ bon C-7a, presumably via equilibration with an amino-iminium mono­ cyclic intermediate (Scheme 21). This process also intervened when an a-unsubstituted dipolarophile methyl propenoate was employed: after chromatography, a larger proportion of C-7 epimer was observed than might be expected from simple endo : exo selectivity of the cycloaddition. This was accounted for by reversible deprotonation of the amino-iminium ring-opened intermediate to give an enamino ester that underwent con­ jugate N-addition with protonation from either face (Scheme 22). Like­ wise, using methyl (E)-but-2-enoate as dipolarophile afforded the expected cycloadduct, which also epimerized at C-7 on standing. Use of 2-chloropropenonitrile as an alkyne equivalent dipolarophile led to adducts 52 that on further treatment with base underwent a double elimination via a related ring opening and loss of HCl to generate novel N-substituted pyrroles (Scheme 23). When employing dipolarophiles with a sulfone- or sulfoxide-activat­ ing group, we were surprised to find that exo cycloadducts were the major products (Equation (3)), that is, epimeric at C-7 to those illustrated in Scheme 20 (10CAJ461). The relative stereochemistry was secured by Xray crystallographic analyses. We speculate that the extra steric require­ ment of the tetrahedral sulfone moiety may overcome any secondary

Scheme 22

Scheme 23

144

Raymond C.F. Jones

orbital interactions that favor an endo approach for the planar sp2 (carbo­ nyl)-activating groups discussed above. Some secondary products were also observed in low yield when methyl bromoacetate was the alkylating agent, from quaternization of the bridgehead nitrogen atom and elimina­ tive ring-opening.

We were also interested to examine an intramolecular variant of the process, in which the reaction was reduced to a two-component process by tethering the alkylating agent and dipolarophile. Ethyl 5­ (bromoacetoxy)pent-2-enoate (53) was thus reacted with 1-benzyl-2­ imidazoline (44) under the usual conditions, when the expected cycloadduct 54 was not isolated, but instead the pyrrolo[1,2-a]pyra­ zine transformation product 55 was isolated in low yield, from the same eliminative ring-opening, followed by lactone—lactam exchange between the liberated amine and the ester tether (Scheme 24) (98JP12061). When attempting to extend the intramolecular cycloaddition to molecules in which the alkylating agent tethered to a dipolarophile is a bromoketone rather than a bromoester, we observed an unexpected result: the formation of pyrrolo[1,2,3-de]quinoxalines 56 from imidazo­ lines such as 1-benzyl-2-imidazoline (44) (Scheme 25) (01TL3951, 06OBC3155). This was rationalized by assuming initial formation of the expected primary dipolar cycloadduct 57, which then underwent the eliminative ring-opening, formation of enamine 58 (or its regioi­ somer) from the liberated amine, and subsequent prototropic shifts to generate the pyrrole subunit. This mechanism was supported by the isolation in one case of the primary cycloadduct (57; R1 = Ph, R2 = H, R3 = tert-Bu; 31%) using a chiral starting imidazoline (see later for the

Scheme 24

The Annulation of 2-Imidazolines

145

Scheme 25

Scheme 26

chiral series). The relative stereochemistry (secured by an X-ray crys­ tallographic determination) was as expected from our transition state model. Reductive cleavage (NaBH3CN in acidic medium) of the aminal func­ tion in the pyrroloimidazole cycloadducts revealed new N-substituted pyrrolidines 59 that had been formed in diastereoselective fashion (90TL2333, 93JP12391, 98JP12061) (Scheme 26). The pyrrolidine-2,4-dicar­ boxylic acid derivatives 59 (X, Y = carboxylate esters) so produced were of interest as mimics of the neurotransmitter glutamic acid. If the C-2 ester was unhindered, then the secondary amine liberated on cleavage of the imidazoline ring recyclized on standing to form bicyclic lactams, hexahydropyrrolo[1,2-a]pyrazines, e.g., 60. A variant on the alkylation—deprotonation generation of the ylides was observed when the alkylating agent was trimethylsilyl trifluoro­ methanesulfonate and CsF was used as desilylating agent. The cycload­ ducts formed with propenoate derivatives were observed as diastereomer mixtures assumed to be from endo (61) and exo reaction modes (Scheme 27) (90TL2333, 98JP12061).

146

Raymond C.F. Jones

Scheme 27

8. AZOMETHINE YLIDES BY CARBENE INSERTION IN A CATALYTIC CYCLE Most recently, to make the azomethine ylide generation catalytic, and to avoid the need to add base as an additional reagent, we proposed a “cleaner” process, a catalytic cycle (Scheme 28) wherein the active halide-alkylating agent is replaced by a diazo ester and the ylide is formed by insertion of a metal carbenoid onto the imine lone pair of the 2-imidazoline. This proved successful via simultaneous addition of ethyl diazoacetate and fumarate esters (as illustrated) or nitriles as dipolaro­ philes to solutions of 1-benzyl (44) or 1-methyl-2-imidazoline (45) with 10 mol% Cu(OTf)2 as catalyst for carbenoid formation, and in the pre­ sence of 10 mol% Yb(OTf)3 (09TL3577). We speculate that the latter com­ ponent can complex the imine function of the dipole, but its role may also be to activate the dipolarophile. Cycloadducts 62 were isolated from 1­ benzyl-2-imidazoline, which were endo adducts that followed our transi­ tion state model 51; the N-methyl series also afforded the exo adducts as minor products. Double activation of the dipolarophiles seems to be necessary, as ethyl propenoate did not give the expected cycloadduct but rather a fumarate adduct derived from dimerization of the diazoester. A cycloadduct 63, which had unexpectedly undergone oxidation, was observed using N-methylbenzimidazole in this protocol, along with a by-product 64 from proton transfer within the dipole to give an N-heterocyclic carbene (NHC), which couples to the diazo ester-derived

Scheme 28

The Annulation of 2-Imidazolines

carbenoid. Further scoping of this catalytic alternative to alkylation—deprotonation protocol for ylide generation is desirable.

147

the

9. AZOMETHINE YLIDES BY CONJUGATE ADDITION­ PROTON TRANSFER We made a serendipitous discovery when reacting 2-imidazolines 44 and 45 with doubly-activated alkenes such as N-phenyl and N-methylmalei­ mides. Novel cycloadducts 65 were isolated that proved to be 2:1 combi­ nations of maleimide and imidazoline (Scheme 29) (06MI3, 07MI1). Their formation is rationalized by invoking a (reversible) conjugate addition of the imidazoline imine nitrogen atom onto the alkene to form adduct 66, followed by transfer of a proton from the methine group attached to N-3 to the adjacent enolate carbon resulting from the conjugate addition. This forms a more stable formal anionic center and generates the imidazoli­ nium dipole 67, which can then undergo cycloaddition with a second molecule of the doubly activated alkene. The alkene thus functions as

Scheme 29

148

Raymond C.F. Jones

Scheme 30

both Michael acceptor and dipolarophile. The stereochemistry of the 2:1 adducts matches expectation from our transition state model (as in struc­ ture 51), with the nonactivating dipole substituent anti to the imidazoline C-2(H) and an endo mode of approach of dipole and dipolarophile. Minor amounts of exo 2:1 adducts were found. The relative stereochemistries of all these products followed from NOE studies and some X-ray crystal­ lographic analyses. These results were mirrored using other doubly activated alkenes. With fumarate esters, major and minor 2:1 products (68 and 69, respec­ tively) were isolated (Scheme 30); the minor products had the expected relative stereochemistry based on the transition state model, but the major products were C-7a epimers, presumably formed by an aminoimine ring-opening equilibrium, as postulated earlier for other cycload­ ducts (Scheme 20) (98JP12061). Again, NOE studies and crystallographic analyses substantiated the stereochemical assignments. The separated diastereomers underwent re-equilibration in slightly acidic CDCl3 as observed by NMR spectroscopy, so we proposed that the transition state model (as 51) predicts the kinetic product, but that in this instance the thermodynamic product is the C-7a epimer. When maleate esters were used, the same products were found as from fumarate esters, con­ sistent with interconversion of maleate and fumarate, mediated by the reversible initial conjugate addition step. The fumarate/maleate reactions were slower than the maleimide examples, e.g., 48 h vs. 24 h in CH2Cl2 at reflux. Extended reaction times (e.g., 10 days) with fumarates afforded secondary transformation pro­ ducts of the 2:1 cycloadducts, of the type discussed already (98JP12061), such as ring-opening to give enamino esters, and subsequent lactamiza­ tion to form pyrrolo[1,2-a]pyrazines (Scheme 31). The conjugate addition-proton transfer mechanism is supported further by the use of different alkenes as conjugate addition acceptors and dipolarophiles, to form 1:1:1 adducts (e.g., Scheme 32) (06MI3). The slower reaction with fumarates than maleimides suggested an experi­ ment where 1-benzyl-2-imidazoline (44) and dimethyl fumarate were mixed at 20C and an N-substituted maleimide was added slowly. Pre­ suming that the conjugate addition is rate determining, the maleimide

The Annulation of 2-Imidazolines

149

Scheme 31

Scheme 32

undergoes addition fastest, followed by proton transfer to produce a dipole in the presence of a relative excess of fumarate, which acts as dipolarophile. The stereochemistry of these three-component adducts 70 conforms to the standard transition state model. Trace amounts of the 2:1 endo and exo adducts of the maleimide and of the fumarate were, not surprisingly, also isolated. Using fumaronitrile as the “slow” acceptor with 1-benzyl-2-imidazo­ line and the maleimides in the same procedure produced related 2:1 adducts, and a further three-component experiment using fumarate esters and fumaronitrile illustrated that fumaronitrile is the poorer con­ jugate addition acceptor, since the major 1:1:1 adducts had the diester in the dipole portion and the dinitrile in the dipolarophile position.

9.1 Annulation via the conjugate addition route with singly activated alkenes and with alkynes Whilst investigating the conjugate addition-proton transfer approach for 1,3-dipole generation, singly activated acceptors were investigated with only limited success (06MI3). (2-Nitroethenyl)benzene (nitrostyrene) afforded a minor 6-membered annulation product 71, plus a major enamino ester elimination product 72 (Scheme 33). It is assumed that nitrostyrene underwent the conjugate addition but not the proton trans­ fer, and that the initial 1,4-dipole added to a second nitrostyrene mole­ cule, with closure onto the imidazolinium C-2 position, to give the

150

Raymond C.F. Jones

Scheme 33

annulation product and possibly its diastereoisomer in which the oppo­ site stereoface of the second nitrostyrene molecule has been attacked. Clearly, when the annulation product has the bond to C-8(H) anti to the C—N bond at C-8a, the b-elimination is favored. Using dimethylacetylene dicarboxylate as acceptor gives no possibility of proton transfer, so again annulation to a 6-membered ring in 73 was observed in very low yield (Scheme 33). Interestingly, the new 6-membered ring was of the opposite regiochemistry to that expected, suggesting again a ring-opening/ring­ closing transformation from a primary annulation product 74. Despite the low yields, these results all lend support to the mechanism proposed for 2:1 adduct formation (cf. Scheme 29).

10. ANNULATIONS USING CHIRAL IMIDAZOLINES Several parts of the methodologies introduced previously, in particular the dipolar cycloaddition chemistry, have been applied to the synthesis of chiral optically active heterocycles. For this, chiral 2-imidazolines had to be prepared as starting materials, and the 4-phenyl-2-imidazolines were the selected series. Initially this was applied to the 1-benzyl compounds and then also to other N-substituted derivatives via an improved route.

10.1 Synthesis of substrates The commercial starting point was phenylglycine, readily available as both enantiomers. In the first synthesis, the optically pure amino acid was N-protected as its benzyloxycarbonyl (Z) derivative, then coupled with benzylamine to form benzylamide, using a mixed anhydride method (93TL6329, 96TL1707). Removal of the Z group followed by borane

The Annulation of 2-Imidazolines

151

Scheme 34

reduction of the amide afforded the enantiomers of 2-benzylamino-1­ phenylethanamine (75) corresponding to the enantiomer of the phenylglycine starting material that had been used. The diamine enantiomers were separately converted into enantiomerically pure 1-benzyl-4-phenyl­ 2-imidazoline (76) using triethyl orthoformate as the C1 source (Scheme 34; R-series illustrated) (96TL1707). In addition, reaction of this diamine in optically active form with the imidate prepared from ethyl cyanoace­ tate and ethanol—hydrogen chloride afforded the two enantiomeric 4-phenyl derivatives 77 of the enamino ester 11 used as the starting point for many of our earlier annulation sequences (93TL6329). Later improvements to the route included starting with phenylglycyl chloride hydrochloride, now commercially available for the (R)-series, and reacting with methylamine, benzylamine, or aniline to form the corresponding amides. The methylamide and benzylamide could also be formed by reaction of commercial methyl phenylglycinate hydrochlor­ ide (after neutralization) with the relevant amine. Reduction of the amides with lithium aluminum hydride afforded the corresponding Nsubstituted diaminoethanes that were converted into the 4-phenyl-2-imi­ dazolines, N-benzyl (76), N-methyl (78), and N-phenyl (79), using dimethyl formamide diethyl acetal (Scheme 35) (08MI1).

11. OPTICALLY ACTIVE PIPERIDINES VIA ENAMINO ESTER ANNULATION The sequence developed earlier for annulation of the imidazoline enam­ ino ester 11 with a,b-unsaturated ketones (Scheme 9) was applied to the optically active 4-phenyl enamino ester enantiomers 77. Thus conjugate C-addition to but-3-en-2-one was followed by borane reduction to give optically active piperidine enamino esters 80, from which imidazo[1,2-a] pyridines 81 and 82 could be formed oxidatively (Br2—Et3N) or on acid treatment, respectively (Scheme 36; S-enamino ester illustrated)

152

Raymond C.F. Jones

Scheme 35

Scheme 36

(93TL6329). The latter product could also be obtained directly from the conjugate adducts by completing the borane reduction with a sulfuric acid workup rather than the hydrochloric acid workup. Further aminal reduction of 82 by sodium cyanoborohydride and removal of the second­ ary benzylic N-substituent (the residue from the imidazoline ring!) by hydrogenolysis gave the optically active 2-methylpiperidines isolated as N-tosyl derivatives 83. Pent-1-en-3-one afforded (R)-2-ethylpiperidine in similar fashion from the (S)-enamino ester. We have also reported preliminary studies using a chiral (but racemic) 4,5-diphenyl enamino ester analogous to the 4-phenyl compound 77, to produce a piperidine enamino ester, cf. 80 (03ARK(ii)133).

12. DIPOLAR CYCLOADDITION OF OPTICALLY ACTIVE IMIDAZOLINIUM YLIDES When either enantiomer of the optically active 1-benzyl-4-phenyl-2-imi­ dazoline (76) was employed in the alkylation—deprotonation sequence for imidazolinium ylide generation and cycloaddition, using the one-pot

The Annulation of 2-Imidazolines

153

Scheme 37

protocol described earlier, optically active hexahydropyrrolo[1,2-a]imida­ zoles 84 were prepared (96TL1707) (Scheme 37; S-dipole series illu­ strated). Alkylating agents used were methyl and tert-butyl bromoacetates, and suitable dipolarophiles were 2-methylpropenoate and propenoate methyl esters. Reactions using tert-butyl bromoacetate (R2 = tert-butyl) as alkylating agent gave the highest yields observed to date. The cycloadducts were found to derive from an endo diastereose­ lective reaction mode, with an anti-dipole, as predicted from our transi­ tion state model 51, and additional facial selectivity was provided by the 4-phenyl substituent: cycloaddition took place exclusively from the face opposite to the phenyl substituent of the dipole 85. With tert-butyl propenoate or 2-methylpropenonitrile as dipolaro­ phile, some exo cycloaddition (to give the C-7 epimers of the cycload­ ducts) was also observed as minor products. In these cases, epimerization at C-7a also took place, as had been observed in the achiral series (cf. Schemes 21 and 22). This is illustrated for 2-methylpropenonitrile, which afforded major products 86 and minor products 87 (Scheme 38) (96TL1707). To place substituents at C-6 of the pyrroloimidazole, methyl but-2­ enoate proved to be a suitable dipolarophile, and to generate a quatern­ ary center at C-5, ethyl 2-bromopropionate could be used as an alkylating agent, although yields were lower. As usual, relative stereochemistry was secured by NOE studies and X-ray crystal structure determinations. Using a sulfone- or sulfoxide-activated dipolarophile, optically active endo cycloadducts were observed (with just one exception from the exam­ ples studied) as expected from the transition state model, in contrast to the situation discussed earlier (Equation (3)) with achiral imidazoline substrates (10CAJ461).

Scheme 38

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Raymond C.F. Jones

Scheme 39

We have utilized the pyrroloimidazole annulation products as sources of optically active pyrrolidines. Thus sodium cyanoborohydride under acidic conditions afforded aminal reduction of cycloadducts 88 (Scheme 39); when the C-5 ester was ethyl or methyl, the liberated secondary amine cyclized to produce pyrrolopyrazine lactams 89, but when the ester was more hindered, that is, tert-butyl, N-substituted pyrrolidines 90 were isolated (96TL1711). An unexpected difficulty was encountered in this reduction when pyrrolimidazoles mono-substituted at C-7 were reduced, as this gave pyrrolidines 91 partially epimerized at C-4. This could be minimized by use of excess acid and exactly one equivalent of hydride reagent to afford acceptable ratios in favor of 2,4­ trans isomers. The N-substituted pyrrolidines were not easy to purify, so were directly hydrogenolyzed (Pd(OH)2, H2 at 60 psi, MeOH—TFA) to cleave the benzylic C—N bond and reveal the homochiral pyrrolidines 92, 93. When the C-4 epimer mixtures 90/91 were subjected to hydrogenoly­ sis, some improvement in epimer ratio was observed, implying that 2,4­ cis-substituted pyrrolidines are less stable toward the reaction conditions than the 2,4-trans diastereoisomers. Similar hydrogenolysis of a pyrazine 89 gave pyrrolidine-2-carboxamide 94. Deprotection of pyrrolidine diesters such as 95, prepared as above, was easily accomplished, to give 2,4-dicarboxylic acid 96, which is a naturally occurring potent competitive glutamate transport inhibitor (Scheme 40); our synthesis is shorter than the reported route and also can easily provide analogues. The 2-tert-butyl, 4-methyl ester (95; R = Me, enantiomeric series) undergoes selective reduction at the less-hindered ester and then tert-butyl ester cleavage to give another natural product 97 (Scheme 40). Comparison of our data to the natural materials confirms the stereochemical assignments. Selective manipulation of pyrrolidine

The Annulation of 2-Imidazolines

155

Scheme 40

Scheme 41

diester 98 at C-2 via the acid and aldehyde, on C-2 or C3 chain extensions, led to an optically active pyrrolizidine and indolizidine, respectively (Scheme 41) (96TL1711). The intramolecular mode of cycloaddition was extended into the chiral arena, by the reaction of the 1-benzyl-4-phenyl-2-imidazoline enantiomers (76) with the alkylating agent/dipolarophile 53 described earlier in Scheme 24 (Scheme 42; S-series illustrated). Single enantio­ mers of the tricyclic adduct 99 were isolated in moderate yield (97TL1647). The stereochemistry was confirmed by X-ray crystallo­ graphic analysis and once again conforms to our transition state

Scheme 42

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Raymond C.F. Jones

model. Manipulations of the (S)-imidazoline-derived cycloadduct were accomplished to reveal highly functionalized optically active pyrrolidines. Using the bromoketone-linked dipolarophiles in intramolecular cycloadditions with chiral imidazolines led to optically active pyrrolo [1,2,3-de]quinoxalines 56 as secondary products formed from the expected dipolar cycloadducts 57, as described earlier (Scheme 25).

13. CHIRAL IMIDAZOLINE NITRONES IN CYCLOADDITIONS Imidazolinium oxides (imidazoline nitrones) were prepared in the chiral series. To date these are racemic materials but clearly the potential exists for asymmetric synthesis. Unlike the other 2-imidazolines featured thus far, the nitrones were not prepared from N-substituted-1,2-diami­ noethanes, since attempts to directly oxidize 1-benzyl-2-imidazoline were unproductive. Instead, 2-chloroacetophenone was converted into its tert-butyl oxime ether followed by chloride substitution with benzyla­ mine. The oxime function was reduced using borane with acidic workup to destroy amine—borane complexes, and the tert-butyl group removed by strong acid to afford a hydroxylaminoamine 100 that was stored as its bis­ hydrochloride. Warming the salt with triethyl orthoformate in toluene afforded the 2-imidazoline nitrone salt 101 that was used directly (Scheme 43) (00JHC481, 00SL967). Oxime formation with an optically active O-alkyl hydroxylamine, and/or reduction with an optically active borane-reducing agent, presents two opportunities for future asymmetric synthesis. Treatment of the nitrone salt 101 with base and alkene dipolarophiles such as maleate esters and maleimides led to imidazo[1,2-b]isoxazole cycloadducts 102 and 103, respectively, whose stereochemistry was as usual determined by NOE studies and an X-ray crystal structure (Scheme 44) (00JHC481, 00SL967). The relative stereochemistry observed corresponded to an exo approach mode, with facial selectivity (as

Scheme 43

The Annulation of 2-Imidazolines

157

Scheme 44

expected) controlled by, and anti to, the 4-phenyl substituent. The exo mode contrasts with the predominant observations with imidazolinium ylides. Cleavage-recyclization of isoxazolidine rings is a well-known synthetic strategy, and this was demonstrated with the cycloadduct (102; R1 = Me) derived from dimethyl maleate: hydrogenolysis afforded a pyrrolo[1,2-a]imidazole 104 by N—O bond breaking and lactamization with a new 5-membered ring favored over the alternative b-lactam. A crystal structure determination confirmed retention of stereochemistry during this sequence. When singly activated alkenes were used as dipolarophiles, the derived cycloadducts 105 displayed the activating group at C-7 (C-4 of the isoxazolidine ring), regiochemistry consistent with FMO control in a Sustmann type 1 reaction, and with an exo orientation mode (Scheme 45). However, in the case of a-disubstituted alkenes, the C-6 substituted cycloadducts 106 were observed, albeit in lower yield, and with the activating group endo (00JHC481, 00SL967). Alkynes as dipolarophiles with the imidazoline nitrones afforded different products that could be explained as secondary transformation products of primary cycloaddition products. Thus, with 2-alkynoate esters, acyl alkoxycarbonyl enediamines 107 were formed, whereas with alkyne-1,2-dicarboxylates, pyrrolo[1,2-a]imidazoles 108 were the isolated products (Scheme 46) (00CC1949, 00JHC481). The enediamines in solu­ tion presented the enaminoketone tautomer as illustrated; however, stu­ dies of two examples in the solid state showed one to exist in an enaminoketone tautomer with NH—ketone H-bonding, whereas the

Scheme 45

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Scheme 46

other demonstrated an apparent imino-enol tautomer (Equation (4)). These secondary products can be rationalized by loss of the bridgehead H-atom and N—O cleavage in the initial imidazo[1,2-b]isoxazole cycload­ ducts 109, either by a 1,5-sigmatropic H-shift that is not available to cycloaddition products from alkene dipolarophiles (illustrated in Scheme 46) or by an alternative elimination—enolate reprotonation pathway. This provides the enediamines 107, and in the case of doubly activated alkynes, an ester group is then positioned for cyclization to produce the pyrroloimidazoles 108.

14. SUMMARY Our studies have demonstrated various methods of annulation of 2-imidazolines, using both the double nucleophile strategy and the dipo­ lar cycloaddition strategy. Several of the routes have been extended into the realm of chiral and optically active synthesis. In addition many of the annulation products have been demonstrated to be building blocks for onward transformations in heterocyclic synthesis. We contend that further variations, and extended scope, are possible, and that applications of these methodologies will be forthcoming. The author thanks the

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researchers who have contributed to this work (and are acknowledged in the cited references) and the range of funding bodies and pharmaceutical companies who have made this adventure possible.

REFERENCES 71TL2717 78JHC1021 81TL261 84JP12599 86JP1205 88TL5001 88TL5005 89TL5361 89TL5365 90JP1373 90JP1385 90T6449 90TL1767 90TL1771 90TL2333 91JP1953 93JP11085 93JP12391 93TL6329 94T895 96TL1707 96TL1711 97T1111 97T11781 97TL1647 98JOC8107 98JP12061

R. Sustmann, Tetrahedron Lett., 12, 2717 (1971). C. V. Magani and F. J. Villani, J. Heterocyclic Chem., 15, 1021 (1978). M. W. Anderson, R. C. F. Jones, and J. Saunders, Tetrahedron Lett., 22, 261 (1981). M. W. Anderson, M. J. Begley, R. C. F. Jones, and J. Saunders, J. Chem. Soc., Perkin Trans. 1, 2599 (1984). M. W. Anderson, R. C. F. Jones, and J. Saunders, J. Chem. Soc. Perkin Trans. 1, 205 (1986). R. C. F. Jones, M. W. Anderson, and M. J. Smallridge, Tetrahedron Lett., 29, 5001 (1988). R. C. F. Jones and M. J. Smallridge, Tetrahedron Lett., 29, 5005 (1988). R. C. F. Jones and S. C. Hirst, Tetrahedron Lett., 30, 5361 (1989). R. C. F. Jones and S. C. Hirst, Tetrahedron Lett., 30, 5365 (1989). R. C. F. Jones and J. Schofield, J. Chem. Soc., Perkin Trans. 1, 373 (1990). R. C. F. Jones, M. J. Smallridge, and C. B. Chapleo, J. Chem. Soc. Perkin Trans. 1, 385 (1990). H. Ardill, X. L. R. Fontaine, R. Grigg, D. Henderson, J. Montgomery, V. Sridharan, and S. Surendrakumar, Tetrahedron, 46, 6449 (1990). R. C. F. Jones and J. R. Nichols, Tetrahedron Lett., 31, 1767 (1990). R. C. F. Jones and J. R. Nichols, Tetrahedron Lett., 31, 1771 (1990). R. C. F. Jones, J. R. Nichols, and M. T. Cox, Tetrahedron Lett., 31, 2333 (1990). R. C. F. Jones, S. C. Hirst, and I. Turner, J. Chem. Soc. Perkin Trans. 1, 953, (1991). Z.-T. Huang and M.-X. Wang, J. Chem. Soc., Perkin Trans. 1, 1085 (1993). R. C. F. Jones and K. J. Howard, J. Chem. Soc., Perkin Trans. 1, 2391 (1993). R. C. F. Jones, I. Turner, and K. J. Howard, Tetrahedron Lett. 34, 6329 (1993). M. F. Aly, G. M. El-Nagger, T. I. El-Emary, R. Grigg, S. A. M. Mehvally, and S. Sivagnanam, Tetrahedron, 50, 895 (1994). R. C. F. Jones, K. J. Howard, and J. S. Snaith, Tetrahedron Lett., 37, 1707 (1996). R. C. F. Jones, K. J. Howard, and J. S. Snaith, Tetrahedron Lett., 37, 1711 (1996). R. C. F. Jones, J. S. Snaith, M. W. Anderson, and M. J. Smallridge, Tetrahedron, 53, 1111 (1997). R. C. F. Jones, P. Patel, S. C. Hirst, and I. Turner, Tetrahedron, 53, 11781 (1997). R. C. F. Jones, K. J. Howard, and J. S. Snaith, Tetrahedron Lett., 38, 1647 (1997). P. I. Dalko and Y. Langlois, J. Org. Chem., 63, 8107 (1998). R. C. F. Jones, K. J. Howard, J. R. Nichols, and J. S. Snaith, J. Chem. Soc. Perkin Trans. 1, 2061 (1998).

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98T6191 98TL8979 99JP12087 00CC1949 00JHC481 00JP12331 00SL967 00T2061 01TL3951 03ARK(ii)133 04MI1112 04MI2176 05JOC6137 05MI1132 05MI1209 06MI1

06MI217 06MI3 06OBC3155 07MI1 08CHEC-III(4) 510 08MI1 09MI617 09TL3577 10CAJ461 10MI1566 10MI2688 10MI3816

R. C. F. Jones, P. Patel, S. C. Hirst, and M. J. Smallridge, Tetrahedron, 54, 6191 (1998). P. I. Dalko, V. Brun, and Y. Langlois, Tetrahedron Lett., 39, 8979 (1998). J.-H. Zhang, M.-X. Wang, and Z.-T. Huang, J. Chem. Soc. Perkin Trans. 1, 1999, 2087. R. C. F. Jones, J. N. Martin, P. Smith, T. Gelbrich, M. E. Light, and M. B. Hursthouse, J. Chem. Soc. Chem. Commun., 1949 (2000). R. C. F. Jones, J. N. Martin, and P. Smith, J. Heterocycl. Chem., 37, 481 (2000). R. C. F. Jones, P. Dimopoulos, S. C. Coles, M. E. Light, and M. B. Hursthouse, J. Chem. Soc. Perkin Trans. 1, 2331 (2000). R. C. F. Jones, J. N. Martin, and P. Smith, Synlett, 967 (2000). R. C. F. Jones and P. Dimopoulos, Tetrahedron, 56, 2061 (2000). R. C. F. Jones, J. N. Iley, P. M. J. Lory, S. C. Coles, M. E. Light, and M. B. Hursthouse, Tetrahedron Lett., 42, 3951 (2001). R. C. F. Jones and S. C. Hirst, Arkivoc (Arkive for Organic Chemistry) ii, 133 (2003). T. D. H. Bugg, “Introduction to Enzyme and Coenzyme Chemistry” 2nd edn., p. 112, Blackwell, Oxford (2004). T. D. H. Bugg, “Introduction to Enzyme and Coenzyme Chemistry” 2nd edn., p. 176, Blackwell, Oxford (2004) A. I. Meyers, J. Org. Chem., 70, 6137 (2005). J. E. McMurry and T. P. Begley, “The Organic Chemistry of Biological Pathways”, p. 132, Roberts, Colorado (2005). J. E. McMurry and T. P. Begley, “The Organic Chemistry of Biological Pathways”, p. 209, Roberts, Colorado, (2005). T. C. Westfall and D. P. Westfall, in “Goodman & Gilman’s Pharmaco­ logical Basis of Therapeutics” 11th edn. (L. L. Brunton, ed.), Part II, Chapter 10, p.237, McGraw-Hill, New York (2006). G. A. Head and D. N. Mayorov, Cardiovasc. Hematol. Agents Med. Chem., 4, 17 (2006). X. Zhang, Ph. D. Thesis, The Open University, UK (2006). P. M. J. Lory, R. C. F. Jones, J. N. Iley, S. J. Coles, and M. B. Hursthouse, Org. Biomol. Chem., 4, 3155 (2006). M. Sanchis-Amat, Ph. D. Thesis, Loughborough University, UK (2007). V. Yeh and R. Iyengar, in “Comprehensive Heterocyclic Chemistry – III” (A. R. Katritzky, C. A. Ramsden, E. F. V. Scriven, and R. J. K. Taylor, eds.), Vol. 4 (J. Joule, ed.), p. 510, Elsevier, Oxford, (2008). S. Rafiq, Ph. D. Thesis, Loughborough University, UK (2008). G. L. Patrick, “Medicinal Chemistry”, p. 617, OUP, Oxford, (2009). R. C. F. Jones, J. N. Iley, M. Sanchis-Amat, X. Zhang, and M. R. J. Elsegood, Tetrahedron Lett., 50, 3577 (2009). R. C. F. Jones, S. Rafiq, M. R. J. Elsegood, V. McKee, and M. J. Slater, Chemistry – an Asian Journal, 5, 461 (2010). R. H. Garrett and C. M. Grisham, “Biochemistry”, p. 566, Brooks/ Cole, Boston (2010). R. H. Garrett and C. M. Grisham, “Biochemistry”, p. 688, Brooks/ Cole, Boston (2010). R. H. Garrett and C. M. Grisham, “Biochemistry”, p. 816, Brooks/ Cole, Boston (2010).

CHAPTER

5 Recent Advances in the Dimroth Rearrangement: A Valuable Tool for the Synthesis of Heterocycles El Sayed H. El Ashrya,b,c, Said Nadeemc, Muhammad Raza Shahc and Yeldez El Kilanyd

Contents

a

1.

Introduction 1.1 General schemes for type 1 1.2 General schemes for type 2 2. Translocation of Heteroatoms in Fused Heterocycles

(Type 1) 2.1 Rearrangement of pyrazoloheterocycles 2.2 Rearrangement of imidazoheterocycles 2.3 Rearrangement of 1,2,4-triazoloheterocycles 2.4 Rearrangement of 1,2,4-Triazinoheterocycles 3. Translocation of Exo- and Endocyclic Heteroatoms in

Heterocycles (Type 2) 3.1 Heterocycles with one heteroatom in the ring 3.2 Heterocycles with two heteroatoms in the ring 3.3 Heterocycles with three heteroatoms in the ring 3.4 Heterocycles with four heteroatoms in the ring Acknowledgments References

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Chemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt;

b

Fachbereich Chemie, Universitate Konstanz, D-78457 Konstanz, Germany;

c

International Center for Chemical and Biological Sciences, HEJ Research Institute of Chemistry, University of

Karachi, Karachi 75270, Pakistan;

d

Chemistry Department, Faculty of Applied Sciences, Um-Alqura University, Makka, Saudi Arabia

Advances in Heterocyclic Chemistry, Volume 101 ISSN 0065-2725, DOI 10.1016/S0065-2725(10)01005-6


2010 Elsevier Inc. All rights reserved

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1. INTRODUCTION The Dimroth rearrangement (DR) is a translocation of two heteroatoms in a heterocyclic system, with or without changing its ring structure. Such a rearrangement is also known as an amidine rearrangement. The conversion of a heterocycle to a rearranged isomeric product can give one or two isomers via an intermediate, which selectively or specifically forms one of them as the major one. The stability of the rearranged product is the driving force for its formation, which may lead to the preference of one isomer. The heteroatoms which exchange positions in the rearrangement are S, N, O, and Se. The DR can be generalized to give products resulting from “ring open­ ing, ring closing” (RORC) processes leading to the rearrangement. Different authors have suggested mechanistic aspects, either proposed or based on isotopic labeling; when the rearrangement is initiated by the attack of a nucleophile, it is termed ANRORC (addition of nucleophile, RORC), while in the case of an attack with an electrophile it is termed AERORC (addition of electrophile, RORC). Most cases proceed through the ANRORC mechanism. The DR is typically a reversible process (71JHC643, 73JHC755, 99AHC79, 05JOC6034, 01JOC6576, 07TL2041), leading to the thermodyna­ mically most stable product (96H2607). The isomerization mechanism depends not only on the pH of the solution but also on the number of atoms or bulkiness of the substituents (06RCB2247). The imidazopyrimi­ dines with an aryl substituent at the 2-position are thermodynamically more favored than those with the substituent at the 3-position (99AHC79). When a carbonyl group is present in a pyrimidine ring, the rearrangement process is hampered due to its ability to form hydrogen bonds, hence stabilizing the molecule and retarding the rearrangement (06RJO1403). The DR is usually performed under heat, light, acidic, or basic condi­ tions and yields a varied ratio of the two possible regioisomers (99AHC79, 07TL2041). The rearrangement takes place even in neutral solvents such as ethyl acetate, ethanol, dimethyl sulfoxide (DMSO), or dimethylforma­ mide (DMF) such as in the isomerization of the 5-oxo-1,2,4-triazolo[4,3-c]­ pyrimidines, which were rapidly isomerized to the oxo-1,2,4-triazolo­ [1,5-c]pyrimidines (02H631). DR can be divided into two types based on the position of the translocat­ ing heteroatom(s): either both in the ring or one in the ring and the other located in an exocyclic position of that ring. These two types can be general­ ized in the two schemes DR-Type 1 and DR-Type 2, respectively. The DR can take place in any step of a synthetic scheme when the structure of the molecule and the reaction conditions are suitable (97JOC4085, 05JME5728, 06M1543). The DR has been recognized as a general phenomenon in heterocyclic chemistry (55JC4035, 55JC1858, 99AHC79), although the rearrangement was noticed in earlier works (88BCG867, 09AC183). The rearrangement was termed the DR in the early 1960s (63JC1276). Reviews have included

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some aspects of the DR of particular heterocycles (74AHC33, 98AHC57, 99AHC127, 06RJO1403), and a review from our group has compiled the literature to 1995 (99AHC79). This review covers the literature during 1996 to 2008. Some of the old references have been included when needed to emphasize the phenomenon. This review consists of two main sections as in the former review (99AHC79). Thus, the first one includes the translocation of heteroatoms between rings in fused heterocycles, whereas the second one includes the translocation of exo- and endoheteroatoms within a heterocyclic ring. Further division under each section is based on the number and arrange­ ment of heteroatoms.

1.1 General schemes for type 1 1.1.1 Translocation of Heteroatoms in Fused Heterocycles In this type of rearrangement the translocated heteroatom(s) are part of the ring. The translocation process changes the position of the heteroatom or substituent on that ring leading to either a retained or a changed ring structure. The presence of a heteroatom within a five-membered ring and also at an exocyclic position of the adjacent ring is a promoting factor for the rearrangement. The translocation of heteroatoms can take place between two rings of a fused system by three possible pathways, including the opening of the fused heterocycles via a six-membered or a five-membered ring. Pathway a: ring-1 opens at the N–E bond, followed by rotation of the single bond linked to ring-2 and ultimately E closes with F, thus shifting the ring-1 exocyclic heteroatom F
to be endocyclic in the ring. Pathway b: ring-2 opens at the N–X
bond, followed by rotation of the single bond linked to ring-1 and then X
closes with A, thus the exocyclic heteroatom X
on ring-1 becomes exocyclic to the same ring but at another position. Pathway c: ring-2 opens at the F—G bond, and then F closes with X
. The heteroatom G, in the five-membered ring-2, becomes a substituent on ring-1 whereas the other two heteroatoms of ring-2 become a part of the newly formed five-membered ring on cyclization. The rearrangement is promoted by the presence of an amino, hydroxyl, or thiol group (X
H) at the ortho position of heterocyclic ring-2; this group can then be incorpo­ rated in the new ring on recyclization after ring fission. Examples of pathway a, mostly proceed through the ANRORC mechanism. Nucleophilic attack on C1 of i leads to the cleavage of the C—N bond to form ii, which can reversibly be reconverted to i or undergo rotation around the single bond to give iii whose cyclization produces DR product iv. The R group may be alkyl, aryl, amine, thiol, or halide. Thus, an imidazopyrimidine follows this pathway by the action of OH— as a nucleophile to give the rearranged products (01JOC6576, 07TL2041).

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Acid can catalyze the DR leading to RORC, such as in the synthesis of triazolo[1,5-c]pyrimidines obtained from their triazolo[4,3-c] isomers (06RCB2247, 05ACSV429). The instability of a substituted thieno[2,3-e][1,2,4]triazolo[4,3-c]pyri­ midin-5(6H)-one has promoted its rearrangement to the isomeric thieno­ [2,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-ones under neutral conditions at room temperature (05H2683). In pathway b, opening of ring-2 in a phenyl-triazolotriazine led to a diazo-type intermediate that upon cyclization gave the isomeric phenyl­ triazolotriazine. An example of pathway c is represented by the rearrangement of mono- and diaminotriazolopyridines in ethanolic ammonia (99AHC79, 04MC76).

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1.2 General schemes for type 2 1.2.1 Translocation of exo- and endocyclic heteroatoms in heterocyclic rings In this type the translocation of heteroatom X (endocyclic in the ring) and Y (exocyclic to the ring) takes place during the rearrangement. A bulky substituent on the endo heteroatom prefers to be at the exo position after the isomerization. The exocyclic heteroatom Y can be singly bonded and X can have a substituent and a positive charge or be double bonded where either the double bond can move into the ring to adopt aromaticity or it may remain exocyclic but be translocated with respect to X. All the processes are driven by the stability of the product, solvent, aromaticity of the ring, heteroatom valence, and bulkiness of the substituent.

Pathway 2-a is favorable when X is a nitrogen atom. The reaction proceeds in the presence of a base, heat, or even neutral conditions (03MOL467). If both X and Y are nitrogens and R is any substituent, then the rearrangement follows pathway 2-b to form the thermodynami­ cally stable product. Pathway 2-c is adopted when oxygen or sulfur are endocyclic and nitrogen is exocyclic. In these cases the DR leads to thermodynamically stable amides or thioamides (99JOC9493, 01T8305). This type is common in both five- and six-membered heterocycles. The DR can occur in the absence of nucleophile but heating can induce it. Thus, two DR processes of type 1 and type 2 took place on heating bicyclic heterocumulenes to yield imidazole-dione ring via an oxazole one (97JOC4085).

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2. TRANSLOCATION OF HETEROATOMS IN FUSED HETEROCYCLES (TYPE 1) This kind of rearrangement has been found mostly in five-membered nitrogen heterocycles. It is classified according to the number of nitrogen atoms and their positions in the ring, for example, pyrazolo (Section II.A), imidazo (Section II.B), triazolo (Section II.C), and triazino (Section II.D) heterocycles. Triazolo compounds are extensively studied and are classi­ fied according to the fused ring attached with the triazine ring, for example, triazolopyridines (Section II.C.1), triazolopyrimidines (Section II.C.2), triazoloquinazolines (Section II.C.3), and triazolotriazines (Sec­ tions II.C.4 and II.C.5).

2.1 Rearrangement of pyrazoloheterocycles The attempted deblocking of the t-butyl group from pyrazole 1 gave 2, instead of the expected product 4 required for the synthesis of 3. Com­ pound 2 was formed from 1 through a DR type 1-pathway a (Scheme 1) (07BML1376).

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Scheme 1

An alternative route for 4 was started by the conversion of 5 to 6 whose reaction with hydrazine gave 7. Dehydrative cyclization of 7 with N,O-bis(trimethylsilyl)acetamide afforded 4, via a DR by the formation of a nitrile imine-like species that underwent 1,5-electrocyclic cyclization (07BML1376). This rearrangement was followed by alkylation of 4 to afford 8 (Scheme 2) (96JME1164).

Scheme 2

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2.2 Rearrangement of imidazoheterocycles The DR plays a key role for the regioselective synthesis of 3-substituted-2­ aminoimidazo[1,2-a]pyrimidines that led to a combinatorial approach. Thus treatment of 9 with NaOH/H2O at 100C for 24 h yielded a ratio 95:5 of 9 and 10, respectively (07TL2041) (Scheme 3) and no byproducts were detected by liquid chromatography-mass spectrometry (LCMS), and 1H nuclear mag­ netic resonance (NMR). The insolubility of the products was a main problem. The use of H2O/MeOH was critical to reverse ratio to 5:95. Changing the base did not afford better result but an increase in the concentration of the base significantly reduced the reaction time. Mild conditions were necessary to avoid possible decomposition of the intermediates (71JHC643). The reaction was applied to 11 to give 12 quantitatively as the only regioisomer. Selectivity in the cyclization step was not only driven by steric effects but also by the different electronic patterns of the imidazole intermediates due to the presence of an amino group at C-3 (Scheme 4) (07TL2041). Similar treatment of 13 with aqueous sodium carbonate afforded 14 in 55% yield, where a DR of the 3-bromoimidazole moiety occured in addition to the transformation of the –CHBr2 to an aldehyde group (Scheme 4) (01JOC6576). Suzuki coupling of substituted imidazopyrimidines 15 with 16 pro­ duced 17 whose further arylation gave 18. The reactions have taken place without rearrangement due to the anhydrous conditions. On the other hand, a DR of both 17 and 18 yielded 19 and 20, respectively. The rearranged product 19 subsequently underwent a Suzuki coupling to provide 20 (Scheme 5) (05JOC6034). While the DR is typically a rever­ sible process, presence of an aryl group at the 2-position thermodyna­ mically favors that at the 3-position. In compounds 19 and 20, the aryl

Scheme 3

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Scheme 4

Scheme 5

rings are coplanar and thus conjugated with the imidazopyrimidine ring as supported by UV and molecular modeling calculations. How­ ever, such conjugation was not possible with 17 and 18 due to steric interactions between the ortho hydrogens of the aryl ring and the

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5-hydrogen of the pyrimidine ring. This explained the exclusive formation of 19 and 20. Coupling 7-(trifluoromethyl)imidazo[1,2-a]pyrimidine 21 with arylhalides 22, in polar aprotic solvents such as DMF, DMAc, and NMP in the presence of Cs2CO3 and Pd(OAc)2/2PPh3, gave 3-aryl-7-(trifluoro­ methyl)imidazo[1,2-a]pyrimidine 23. However, during the course of the reaction, its concentration decreased and isomerization via a DR occurred to give the regioisomer 2-aryl-7-(trifluoromethyl)imidazo[1,2-a]pyrimi­ dine 24 (Scheme 6) (06OPD398). The action of alkali on ethyl 5-amino-2-methylimidazo[1,2-c]pyrimi­ dine-3-carboxylate 25 caused its conversion to ethyl 5-amino-3-methyli­ midazo[1,2-c]pyrimidine-2-carboxylate 26 (Scheme 7) (99JOC634). 3-Substituted 6H-imidazo[1,2-c]quinazolin-5-ones 27 underwent a DR to the thermodynamically more stable 2-substituted 6H-imidazo [1,2-c]quinazolin-5-ones 28 by the action of HCl in methanol. This stability was said to be due to the presence of the carbonyl group in an eclipsed position to the large substituent on the imidazole ring in 27 but only with a hydrogen atom in 28 (Scheme 8) (96H2607).

Scheme 6

Scheme 7

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Scheme 8

2.3 Rearrangement of 1,2,4-triazoloheterocycles 2.3.1 1,2,4-Triazolopyridines

Treatment of 1,2,4-triazolo[4,3-a]pyridine 29 with an acid yielded 1,2,4­ triazolo[1,5-a]pyridine 30 (Scheme 9) (05JME5728).

2.3.2 1,2,4-Triazolopyrimidines

When 4-aryl(alkyl)-1-(4,6-dimethylpyrimidin-2-yl)thiosemicarbazides 31 reacted with methyl iodide in boiling methanol in the presence of sodium acetate, they gave 2-R-amino-5,7-di-methyl[1,2,4]triazolo[1,5-a]pyrimi­ dines 34 in high yield. The first step could be the alkylation of the sulfur atom with the formation of 32 followed by intramolecular cyclization with elimination of methanethiol to give 33. The subsequent DR of 33 gave 34 (Scheme 10) (06RJO1403). Treatment of 1,2,4-triazolo[4,3-c]pyrimidin-5(6H)-ones 35 with base gave [1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-ones 37 via a DR, whereby the pyrimidine ring in 35 was cleaved to give the triazole ester inter­ mediate 36 that survived under these conditions (Scheme 11) (99JCS(P1) 1333). But in aqueous sodium hydroxide, the DR did not occur and a

Scheme 9

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Scheme 10

Scheme 11

decarboxylation presumably took place, which led to degradation of pro­ ducts. In neutral solvents, such as ethyl acetate, ethanol, DMSO, or DMF, the DR took place. On the other hand, 35 at room temperature was quite stable for several days in trifluoroacetic acid (TFA) or concentrated HCl, but gradually were isomerized in glacial acetic acid within one day (02H631). Thus, the synthesis of 35 encountered confusing results due to rearrange­ ment. The occurrence of a DR was supported by the crystal structure of 37. An unexpected participation of the cyano group has been reported during the DR of 6-cyano-7-phenyl-1,2,4-triazole[4,3-a]pyrimidin-5(8H)­ one to give 7-imino-5-phenyl-1,2,4-triazolo[1,5-a]pyrimidine (98ZN1203). The thieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-ones 39 were too unstable to be isolated even in neutral solution at room temperature

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Scheme 12

but rearranged directly to the 2-substituted thieno[2,3-e][1,2,4]triazolo [1,5-c]pyrimidin-5(6H)-ones 40 (Scheme 12) (05H2683). The two pathways for 40, from the hydrazine 38 on refluxing with triethoxy alkane or from its hydrazone by reflux in the presence of chloranil, never led to the isolation of the expected product 39 but each time led to the isomerization to 40 through a DR (Scheme 12) (08H777). The cyclization of 4-hydrazino-2-methylthio-thieno[2,3-d]primidines with one carbon-inserting agent gave the triazolo[4,3-c]pyrimidines 41. They resist the isomerization in acid, but undergo a DR to the [1,5-c] isomers 42 under basic conditions using NaOMe or hydrazine; the DR product was confirmed by X-ray analysis (08JCR336). The rearrangement of analogs of 41 to 42 can take place in both alkaline and acidic media (Scheme 13) (06RCB2247). Heating aminoimine 43 and hydrazino-pyrimidine 43a with acid chlorides (R = H, CH3, Et, Pr, or Bu) in cholorobenzene and catalytic amount of DMF gave 44 and 45, but by refluxing 45 in an aqueous ethanolic solution of NaOH afforded 44 via a DR. The rearrangement

Scheme 13

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Scheme 14

also occurred in acidic media through an ANRORC mechanism, con­ firmed by quantum chemical calculations. Substituents on the triazole ring were found to play the principal role in the rearrangement (Scheme 14) (06RCB2247). The triazolo[1,5-c]pyrimidine 46 and 49 were obtained directly via the DR of their respective triazolo[4,3-c]pyrimidines, formed by cyclization of the hydrazone 47 and its acetate 48, which upon deacetylation afforded 50 (05ACSV429). The DR product 46 was verified with X-ray diffraction, and its formation was said to be due to hydrolysis of the hydrazine residue followed by cyclization of the resulting hydrazone with DMF in boiling acetic acid (Scheme 15) (05HAC226). The tricyclic 1,2,4-triazolopurin-5(6H)-ones 51 (R = H, Alkyl, or Aryl, X = O or S) and pyrazolo-1,2,4-triazolo[4,3-c]pyrimidin-5(6H)-ones 53 were easily rearranged into 52 and 54, respectively (Scheme 16) (02H631). The DR can be induced thermally in acid, alkali, and neutral media (78AJC2505). When compound 55a reacted with excess hydrazine hydrate at room temperature, it underwent a DR to give 1,3-diphenyl-4-hydrazino-pyrazolo [3,4-d]-pyrimidine 55. The respective N-(1,3-diphenylpyrazolo[3,4-d]pyri­ midin-4-yl)hydrazones were prepared by condensation with aldehydes. Treatment of the hydrazones with iron(III) chloride in ethanol gave as a single product 3-substituted-7,9-diphenylpyrazolo[4,3-e][1,2,4]triazolo [4,3-c]pyrimidines 56 (Scheme 17). The conversion is similar to other related

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Scheme 15

Scheme 16

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Scheme 17

oxidative cyclization of aldehyde N-heteroarylhydrazones with iron(III) chloride, which have been reported to proceed via the generation of their respective nitrilimines, which then through an in situ 1,5 electrocyclization afforded the respective fused heterocycles. When 56 were heated in ethanol and sodium acetate, they isomerized to the thermodynamically more stable pyrazolo[4,3-e][1,2,4] [1,5-c]pyrimidine derivative 57 through tandem ring opening and ring closure reactions (08T10339). Derivatives of the pyrazolo[3,4-d][1,2,3]triazolo[1,5-a]pyrimidines 59 were synthesized from the corresponding angular isomers 58 through a DR, in quantitative yields (Scheme 18) (08TL5125). The 1,2,4-triazolo[4,3-c]pyrimidinone nucleoside 61 was prepared from 60 by hydrazinolysis and subsequent acetylation to give N4-acetylamino-20 ­ deoxycytidine 60a where acid promoted its cyclization to give 61. The basic conditions required for the deprotection of 61 caused its rearrangement to its

Scheme 18

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Scheme 19

isomer 6-(4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2,8-dimethyl­ [1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one 62 (R = H). Alternatively, the latter isomer 62 was prepared by the amination of diacetyl-5-methyl-deoxycyti­ dine 63 using 2,4-dinitrophenoxyamine to give the 3,4-diaminopyrimidi­ none 64 whose reaction with trimethylorthoacetate or acetic anhydride led to the triazolopyrimidinone 62 (R = Ac) (75CPB844). Interestingly, acetyl 60 did not rearrange or cyclize under basic conditions with methoxide ion (Scheme 19) (99JCS(P1)1333, 98TL3865).

2.3.3 1,2,4-Triazoloquinazolines

The 2-thio[1,2,4]triazolo[1,5-c]quinazoline 66 was obtained by treatment of 4-hydrazinoquinazoline 65 with potassium ethyl xanthogenate via a facile in situ DR of the expected triazolo[4,3-c]quinazoline. The potassium salt that converted to 66 with dilute HCl has an 1H NMR spectrum in DMSO-d6 solution indicating its existence in equilibrium with the thione tautomer. Its structure was established by X-ray diffraction and con­ firmed by an independent synthesis (Scheme 20) (06M1543). When the potassium salt was treated with alkylhalides, phenacyl chloride, or

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Scheme 20

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El Sayed H. El Ashry et al.

chloroacetic acid under mild conditions, the alkylation was found to proceed smoothly at the sulfur atom to give 66a (06M1543). A series of 4-cyclohexyl-1-substituted 1,2,4-triazolo[4,3-a]quinazolin-5-(4H)-ones 67 were treated with potassium hydroxide in boiling ethanol to yield the DR product 67a (Scheme 20) (08H1479). The reaction of 68 with triethyl orthoformate under reflux at 140C gave 7-chloro-4-phenylamino[1,2,4] triazolo[4,3-a]quinazolin-5(4H)-ones 68a, which were heated in pyridine and xylene at 180C but no isomerization occurred. Careful investigations revealed that the reaction of 68 directly with the orthoformate at 180C afforded 68b suggesting that DR occurred under these reaction conditions (Scheme 20) (08H2421).

2.3.4 1,2,4-Triazolo-1,2,4-triazines

Heating 6-aryl-1,2,4-triazin-3(2H)-ones 69 with carboxylic acid hydra­ zides in nitrobenzene-containing triethylamine gave 1,2,4-triazolo[1,5-d] [1,2,4]triazin-5(6H)-ones 71 (Scheme 21). During the course of the reaction several intermediates including 70 were formed (04RJOC85). This rear­ rangement readily occurred either under basic conditions (77AJC2515) or thermally in boiling nitrobenzene (66JC2031).

2.3.5 1,2,4-Triazolo-1,3,5-triazines

Thermolysis of both 72 and 75 at 350C was accompanied by a DR to yield 3,6,10-triphenyl-tris[1,2,4]triazolo[1,5-a:10 ,50 -c:400 ,300 -e][1,3,5]triazine 73. However, thermolysis of 72 at 240C did not give 75, but its ring-

Scheme 21

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181

Scheme 22

opened product 74 gave 75 under thermolysis at the same temperature (Scheme 22) (05RCB719).

2.4 Rearrangement of 1,2,4-Triazinoheterocycles When 4-hydrazinoquinazoline 65 was allowed to react with a-keto­ carboxylic acids or their esters 76 in 2-propanol, the corresponding hydrazones 77 (R1 = H) and 78 (R1 = Et) were isolated in good yields. Their cyclocondensations in acetic acid afforded the 3-substituted 2-oxo-2H-1,2,4-triazino[2,3-c]quinazolines 80 (R = CH3, Ph, 2-thienyl) apparently through facile DR intermediates, triazino[4,3-c]quinazo­ lines 79 (Scheme 23) (07H619).

3. TRANSLOCATION OF EXO- AND ENDOCYCLIC HETEROATOMS IN HETEROCYCLES (TYPE 2) This type of DR is versatile in both five- and six-membered heterocycles. The heteroatoms are not restricted to nitrogen but may also be sulfur, oxygen, or selenium. Two heteroatoms are involved; one must be

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Scheme 23

exocyclic at the ortho position of the endo heteroatom-containing hetero­ cycle. This type can be classified according to the number of heteroatoms, from one to four heteroatoms in the ring. The DR also occurrs in natural compounds like DNA and other nitrogenous bases, such as pyrimidines and purines. This part is divided according to the heteroatom(s) present in the ring where translocation occurs.

3.1 Heterocycles with one heteroatom in the ring Heterocycles with one heteroatom include furans, isoquinolines, pyrans, and thiopyrans that will be discussed here.

3.1.1 Furans Functionalized furans can undergo a DR as such or after their presumable formation as intermediates. Thus, the furans 81, which are rarely used

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183

Scheme 24

but are accessible species, allow a facile synthesis of substituted 3(5H)­ pyrrolin-2-ones 82 via a DR (Scheme 24) (01CL738). A domino cycloaddition-DR sequence takes place during the synth­ esis of pyrrolin-2-ones from N-isocyanides. Thus, methyl acetylene dicar­ boxlate with isocyanide 83 and aromatic aldehyde 84 gave furans 86 via intermediate 85. Rearrangement of 86 gave 88 via the open chain inter­ mediate 87 (Scheme 25) (03ACR899).

Scheme 25

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Scheme 26

Regioselective cyclization of oxalic acid-bis(imidoyl)dichloride 89 and the dianion derived from 2-acetyltetralone 90 led to intermediate 91, which subsequently rearranged to 92 by the translocation of N and O atoms (Scheme 26) (04SL2779). Dilithiated 4-(phenylimino)pentan-2-one, generated from 93, with oxalic acid bis(imidoyl)dichloride 94 resulted in regioselective cyclization and formation of 95 as an inseparable 1:1 mixture of E/Z isomers. On standing, the yellow-colored solution of 95 changed slowly into the redcolored isomer 5-alkylidene-2,5-dihydropyrrol-2-one 96 (12%, low con­ version) formed by a DR (Scheme 27) (04EJO1897). The yield of 96 was

Scheme 27

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Scheme 28

improved (56%) by the addition of two equivalents of lithium chloride to the reaction. The rearrangement proceeded sterioselectively and afforded the E-isomer exclusively. Ethyl acetoacetate 97 with oxalic acid bis(imidoyl)chloride 89 (R = p—MeO—C6H4) gave the 5-alkylidene-5H-pyrrolin-2-one 98 (Scheme 28) (01SL1437, 04EJO1897). The reaction can be explained by a regioselective attack of the terminal carbon atom of the dianion of 97 onto the dielectrophile 89 and cyclization mediated by the oxygen atom to give intermediate 99, which then underwent a DR to 98. The domino cycliza­ tion/DR proceeded with excellent E/Z diastereoselectivity due to the stereodirecting effect of the substitituent attached to the pyrrole nitrogen atom, which is present in 96 and 98 but not in 95 and intermediate 99. The rate of the DR was enhanced by the Lewis acid LiCl formed during the cyclization. The cyclization of the dianion of phenylacetic acid 100 with oxalic acid-bis(p-tolylimidoyl)dichloride 94 afforded maleic imide 103 by an initial cyclization to give intermediate 102 and subsequent DR (Scheme 29) (98SL399, 01CEJ2617, 04CRV4125). The 3-amino-1-azadiene complex 104 underwent a ring-closure reac­ tion to give the unstable intermediate 105 that rearranged to 106. A subsequent DR either before or after decomplexation afforded 5-ylidene­ pyrrol-2(5H)-ones 107 (Scheme 30) (99JOC365).

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Scheme 29

Scheme 30

Acid-catalyzed DR of 108 in the presence of TsOH/H2O/CHCl3 gave 65% yield of tripyrroline 109 (Scheme 31) (99JA1958) as an inseparable mixture of E- and Z-isomers (84CHEC94). Similarly, Pd(0)/CuI-mediated coupling of semicorrin with an alkyne amide formed tricyclic

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Scheme 31

Scheme 32

iminolactone 110 in 60% yield. Analogous to 108, iminolactone 110 was converted to the tripyrroline 111 (60%; Z:E = 3:1) on acid-catalyzed isomerization. Similarly, furamine 112 was converted with acid to the pyrrolidines 113 via a DR (Scheme 32) (99JOC1778). Also, 114 gave 116 via ring open­ ing to the keto-amide 115, which was followed by cyclodehydration to yield 116 (Scheme 33) (00JOC205).

3.1.2 Isoquinolines

Reaction of 117 labeled with an 15N isotope in the amino group and 4-methylbenzaldehyde yielded hydrazone 119 where the 15N atom was found in the ring. The change in the position of the isotopic label sup­ ported the idea that the reaction proceeded through a DR. As further proof 117 was reacted with the aldehyde in acetonitrile in the absence of base in order to hinder the rearrangement. After a 5-h reflux postulated intermediate 118 was obtained in considerable yield. Treatment of this compound with DBU in ethanol then afforded 119 revealing that the azomethine salt was most probably an intermediate during the rearran­ gement of 117 to 119 (Scheme 34) (08T1101).

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Scheme 33

Scheme 34

3.1.3 Pyrans

A DR of 6-amino-4-oxopyrano[3,4-d][1,2,3]thiadiazoles 120 gave 6-hydroxy-4-oxo-[1,2,3]thiadiazolo[4,5-c]pyridines 123 under thermal conditions. The rearrangement proceeded by the opening of the pyran ring to the ketene intermediate (s-cis) 121 followed by simultaneous rotational isomerization to 122 (s-trans) and then recyclization to form the pyridin-2-one 123. The calculated energy barriers [B3LYP/6-31G(d)] were used to support the experimental results (Scheme 35) (05EJOC2914). The intermediate of 2H-pyran-2-imine 125 was identified by spec­ troscopic methods during the synthesis of 2(1H)-pyridones from b-enaminones 124 by a reaction with malononitrile. Ring opening by action of a nucleophile afforded 126 that cyclized to 2(1H)-pyridone 127. The transformation via 126 was considered to be a DR (Scheme 36) (99JOC9493).

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Scheme 35

Scheme 36

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El Sayed H. El Ashry et al.

3.1.4 Thiapyrans The conversion of 5,6-dihydro-N-phenyl-2-(phenylimino)-2H-thiopyran­ 4-amine 128 (R = iPr or Ph) to 1,2,5,6-tetrahydro-2-methylene-N,1-diphe­ nyl-4-pyridinamine 130 occurs by a DR under thermal conditions through intermediate 129 (Scheme 37) (01T8305).

3.2 Heterocycles with two heteroatoms in the ring 3.2.1 Pyrimidines The presence of a DR in pyrimidine rings again has attracted much attention as shown earlier (99AHC79). The synthesis and reactions of purines and their nucleosides, as well as kinetic studies of the DR, have been reviewed (96YZ355). The reaction of 2-amino pyrimidine with ethyl bromoacetate gave a mixture containing 132 presumably as a product from a DR (Scheme 38) (03MOL467). Protonated cytosine and 5-hydroxy as well as 5-hydroxymethyl­ cytosine, but not its 5-formyl-substituted analog, undergo a DR in the gas phase. The loss of HNCO from the [M þ H]þ ion of [1,3-15N]cytosine required a rearrangement of the cytosine component before the elimination (06JAM1335). Adenosine can undergo a DR to exchange the exocyclic N6 and endocyclic N1 atoms. Theoretical predictions and experimental data unequivocally supported ring cleavage between N1 and C2 followed by

Scheme 37

Scheme 38

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Scheme 39

rotation about the C4—C5 bond, ring closure, and proton migration (75BBR581, 05JAM1713). Although the literature is varied in the case of a DR of unmodified cytosine, or cytidine, the rearrangement of N3-substi­ tuted cytosine during acetylation has been observed (64JOC1770, 65JOC2766). Moreover, this type of rearrangement has been employed for the synthesis of 15N3-labeled uridine (65B54) and cytidine (04JOC8148) from the 15N4-substituted cytidine N3-oxide. Protonated cytosine under­ went a similar rearrangement, which allowed the switching of N3 and N4 in the gas phase and facilitated the loss of unlabeled HNCO from [1,3-15N] cytosine (133 to 134). In this regard, a proton on cytosine at N3 resembles to some extent a substituent at N3, which results in weakening of the N3—C2 bond that facilitates the rearrangement (Scheme 39) (06JAM1335). Semi-empirical calculations at the AM1 level predict that the gasphase proton affinities of N3 in 20 -deoxycytidine-50 -monophosphate and 20 -deoxycytidine-30 -monophosphate are higher than those of O2 in the corresponding nucleotides by 2.5 and 3.9 kcal/mol (00JAM24). On the other hand, high-level ab initio calculations with the inclusion of correlation effects at the Møller—Plesset level predicted that three atoms (N1, N3, O2) in neutral cytosine are susceptible to protonation within a range of 1 kcal/mol (96JA6811). Furthermore, recent calculations sug­ gested that the transition-state energies for proton migrations between O2 and N3 of 1-methylcytosine are much smaller than the energy required for the major cleavage reactions (05JMP1417). Similar to the dissociation of uracil (94JAM339), ammonia can be lost from N3 of cytosine. Alternatively, ammonia can originate from the N4 nitrogen. The percentage of the product resulting from a DR can be esti­ mated to be ~25% from the relative abundances of the product ions derived from the loss of HNCO. On the other hand, ~40% of the lost ammonia does not bear the 15N label. Therefore, a DR cannot account completely for the elimination of unlabeled NH3 from [1,3-15N]cytosine; a small fraction of the ammonia, therefore, must be lost from N4. Thus the DR made it somewhat complicated to ascertain the origin of the site of loss of NH3. The collisional activation of the [M þ H]þ of 5-hydroxymethyl-2-deox­ ycytidine (5-HmC) led to the facile cleavage of the glycosidic bond. Further fragmentation of the protonated 5-HmC resulted in the

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Scheme 40

predominant loss of a H2O molecule, and the resulting ion can readily eliminate a HNCO component upon further collisional activation. The loss of both HNCO and H15NCO from the [M—H2O]þ ion of 135 or 136 can be attributed to a Dimroth-like rearrangement (Scheme 40) (06JAM1335). The relative abundances of these two ions may show that ~40% of the ion of m/z 124 has undergone such a rearrangement, which was higher than that found for the protonated deoxycytidine. A DR was largely prohibited for protonated 5-formyl-methylcytidine (5-FmC), which necessitated protonation of N3 because the presence of a 5-formyl group rendered protonation of N3 most unlikely. Intramolecular hydrogen bonding led to facile protonation on the exocyclic 5-carbonyl group. The difficulty in protonating N3 prevents the elimination of NH3 from the [M þ H]þ of 5-FmC. Further fragmentation resulted in a facile loss of CO, though the expulsion of HCN constituted a minor fragmenta­ tion pathway. The fragmentation demonstrated the loss of only HC15N, supporting that HCN was selectively eliminated from the N1 position (06JAM1335). 15 4 N -Labeled cytidine N3-oxide 137 (R = OH) was treated with a slight excess of benzyl bromide in the presence of lithium methoxide to give the DR product 15N4-labeled uridine 4-O-benzyloxime 138 (R = OH) in 95% yield (Scheme 41) (04JOC8148). The key intermediates are 139 and 140. Their ring opening gave 141 that recyclized to 138. Similarily, [3-15N,4-15NH2]cytidine was synthesized from the 4-oxo of uridine or N3-activated uridine followed by a DR (00JOC2827). When 142 was treated with 1-amino-2-hydroxypropane 143 in etha­ nol, the expected product of the DR via ring opening was 6-amino-3­ methyl-5-(N-2-hydroxypropyl)iminomethyl)-1-(4-nitrophenyl) uracil 144 in 51% yield (Scheme 42) (04TL8007). To establish the influence of solvent on the outcome, the reaction was conducted in 2-hydroxypropane and t-butanol. A mixture of DR product 144 and ANRORC product 145 was obtained in molar ratios of 3:1 and 4:1, respectively (total yield 90%). However, the opposite ratio 1:5 (total yield 96%) of DR/ANRORC pro­ ducts was obtained using DMF containing 10% of water. Apparently after the addition of the amino group to C6 of the uracil and ring opening in protic solvents, addition of a proton to the nitrile nitrogen atom made the

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193

Scheme 41

latter more susceptible to attack by the NH-nitrogen leading to 144 (Scheme 42, path a). But when an aprotic solvent was used, attack of the nucleophile on the carbonyl gave the ANRORC product 145 (Scheme 42, path b) (04TL8007).

3.2.2 Pyrrolopyrimidines Heating 3-(3-chlorophenyl)-5,6-dimethyl-4H-pyrrolo[2,3-d]pyrimidine-4­ imine 146 in ethylene glycol, ethanol, or water gave 4-(3-chloropheny­ lamino)-5,6-dimethyl-7H-pyrolo-[2,3-d]pyrimidine 147 in 92% yield via a DR (Scheme 43) (01OPD581). 3-Amino-4-imino 7H-pyrrolo[3,2-e][1,2,4] triazolo[1,5-c]pyrimidine 148 was synthesized from 2-ethoxymethyle­ neamino-1H-pyrrole-3-carbonitrile and hydrazine hydrate transformed by alkali into hydrazinopyrimidine 149 via a DR. Reaction of 149 with acid chlorides gave pyrrolotriazolopyrimidines 150 (R = H, Me, or Et) that underwent a DR to give 151 on heating for several hours in aqu­ eous ethanolic alkali. Under similar conditions, 150 with bulkier

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Scheme 42

substituents R very easily rearranged into isomers 151. The steric pres­ sure of bulky substituents decreases the energy required for a DR of 150 to 151 (Scheme 43) (06RCB1492).

3.2.3 Thienopyrimidines 7-Amino-4-[(4-methylphenyl)a mino]pyrido-thieno[3,2-d]pyrimidine­ 8-carbonitriles 153 were synthesized from 152 via a DR (Scheme 44) (07HTC405).

3.2.4 Pyrazolopyrimidines Monosubstituted hydrazines reacted with ethyl N-4-cyano-1-(4-substituted)­ 1H-pyrazol-5-ylformimidate 154 to afford a mixture including the DR product 155. Similarly, 154 with m-anisidine afforded only the DR product 156 (Scheme 45) (07ARK92).

3.2.5 Imidazopyrimidines The alkylation of imidazopyrimidines may involve initial attack at N1 that on a DR gave the N6 adduct. Thus, the base-catalyzed cleavage of the six-membered ring in 157 gave a ring-opened intermediate that upon recyclization interchanged the locations of the endo- and exocyclic

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Scheme 43

Scheme 44

195

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Scheme 45

nitrogens to give 158 (00CRT625). A DR of 159 took place under harsh conditions using Me2NH to give 160 (Scheme 46) (05CC3968). When DNA was treated in vitro with styrene oxide, significant quan­ tities of deaminated products were detected. The initial alkylation on the N1 and N6 positions of adenine in DNA was difficult to estimate due to the instability of the styrene oxide-induced N1 adducts. The N1 adducts were prone to either a DR to the corresponding N6-adenines or deamina­ tion to the corresponding hypoxanthine adducts (00CRT18, 00CRT625, 07CRT790). Under alkaline conditions, a DR was the sole pathway, whereas deamination prevailed at pH 6. The rate of DR of 1-substituted deoxyadenosine-styrene oxide adducts was slower than that of the riboside analogs resulting in greater yields of the deaminated compounds. The DR from 161 to 163 has a competing deamination process to give 162 (Scheme 47) (92JBC23427, 98CRT838). Alkylation of the adenine N1 164 with the oxirane 165 can occur at both the carbon atoms anchoring the ring. Reaction at the internal carbon resulted in the formation of stereoisomeric N1-(1-hydroxy-3-buten-2-yl)­ 20 -deoxyadenosine adduct 166 (Scheme 48) (05B3327), which can subse­ quently undergo deamination to the corresponding deoxyinosine adduct 167, or a DR to the corresponding N6-adducts 168 (96CRT875, 99IARC123, 00EMM48). Reaction of adenine N1 169 at the terminal epoxide of 165 gave an unstable intermediate 170 (06CRV607), which underwent deamination to 171 (96CRT875) or DR to 172 (Scheme 49) (95CRT389).

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Scheme 46

Scheme 47

The incubation of 174a that tautomerizes with 173 gave products which by high-performance liquid chromatography analysis were found to be 175a resulting from a DR (Scheme 50) (99OL1233, 00B924). Adenine N1-adducts 174b from butadiene diol epoxides formed from human metabolism of butadiene diol (99CRT566, 05CRT145) gave N1 adducts 175b (95CRT389, 00CRT625) and 174c gave 175c (99B13338). Similarly, 174d formed 175d under alkaline con­ ditions, whereas at pH 6 deamination prevailed (95CRT389, 98CRT838, 00CRT421, 01B9780).

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Scheme 48

Scheme 49

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Scheme 50

The deoxyadenosyl-N6-butadiene triol 175e adduct identified in Chinese hamster ovary cells (94CG1903) resulted from a DR of 174e. Analogous chemistry was described for the reactions of styrene oxide with adenine N1 (97CRT1247, 04CRT1007). 1-Isopropyladenine 174f gave 175f under basic conditions (04CRT1531). The N1-adenine 174g gave 175g, or a deamination to N1-hypoxanthine (98CRT838). Adenine under­ went a DR even at neutral conditions (95CRT389). The N1-3,4-epoxy-1­ butene adenine 174h adducts detected as precursors of previously reported N6-adenine 175h adducts (95CG2999) formed through a DR (97CG137). Under mild conditions (50C, pH range 6—7) 15-N6-labeled adenosine 174i was converted to N6-adenosine 175i (95H1399). An N6-(3­ iodobenzyl) group was introduced in aristeromycin 174j to give 175j (00JME2196). Oxidizing and then O-alkylating the N1 position of adenosine gave 174k. Subsequent base-mediated ring-opening hydrolysis and then ring closure swaps the positions of the N6-exocyclic amine and the derivatized N1 nitrogen, thereby installing the N-alkoxy functionality at the N6 in 175k (07CB299). 2-Deoxyadenosine with recemic (1-chloroethenyl)oxirane gave the initial adduct 174l, which hydrolyzed to 175l (02CRT1549). Similar results

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El Sayed H. El Ashry et al.

Scheme 51

have been reported for the N1 adducts of ethenyloxirane (96CRT875), styreneoxide (98CRT838), and ethyleneoxide (92MI35). Under basic con­ ditions 174m gave 175m quantitatively (01JA8750). The N6-(2-methylbenzyl) derivatives 179a–d were synthesized by the alkylation of 176c at N1 by 2-methylbenzyl bromide to give 177, which rearranged under basic conditions to 178a–d whose deprotection gave 179a–d (Scheme 51) (95CRT389, 98CRT838, 00CBI201, 01CBI111, 04MI379, 05CAB237). Treatment of 15N4-labeled cytidine N3-oxide and 15N4-labeled 2­ deoxycytidine N3-oxide, prepared from the appropriate unprotected uri­ dines in three steps, with benzyl bromide in the presence of excess lithium methoxide allowed a smooth DR even under mild conditions leading to 15N3-labeled uridine 4-O-benzyloximes, which easily under­ went reductive N—O bond cleavage to give 15N3-labeled cytosine nucleo­ sides in high yields (04MI379). The nucleoside analogs 180 undergo rearrangement at pH 13 to chro­ mophores consistent with N6-substituted adenosines 181 and 182 (03CRT1328, 04CRT717).

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201

Scheme 52

A DR of N1-alkyladenines 183, isolated from calf thymus DNA, was quantitatively converted to 184 at basic pH (Scheme 52) (04CRT950). When 185 was heated at pH 12 overnight, it gave 186 (04CRT1638). 1,3-Butadiene (BD) is classified as a known human carcinogen based on epidemiological evidence in occupationally exposed workers and its ability to induce tumors in laboratory animals. Under physiological conditions, the BD-adduct 1-(guan-7-yl)-4-(aden-1-yl)-2,3-butanediol 187 afforded 188 along with its deaminated product 188A via a DR (Scheme 53) (08CRT1163). The marine ascidian purine aplidiamine and its 9-b-D-ribofuranoside, a derivative of naturally occurring 8-oxadenine, were synthesized by alkylation of 8-oxadenosine 189 (Y = OH) with 4-benzyloxy-3,5­ dibromobenzyl bromide to give the N-alkylated analog. A subsequent DR by heating in boiling NaOH produced product in 58% overall yield. Further acid hydrolysis gave 190 (Scheme 54) (98TL4695).

Scheme 53

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El Sayed H. El Ashry et al.

Scheme 54

Scheme 55

A DR of the N1-adduct 191 to 192 was noticed during its isolation (98H359). The rearrangement was consistent with a slight change in gel mobility of the interstrand cross-link that was observed on piperidine treatment (Scheme 55) (05JA3692). Matrix-assisted laser desorption ionization-time of flight (MALDI­ TOF) mass spectrometry could not determine whether oligonucleotide conversion had taken place during storage or under genome construction conditions (04PNA14051). The nucleotide 194 was formed by treating 193 with 1-ethyl-3-(3-dimethy-lamino)propyl carbodiimide hydrochloride (EDC) at pH 10 (94JA7481). (Scheme 56) The labeled N1-oxide nucleoside was methylated with methyl iodide or dimethyl sulfate and then followed by treatment with dimethylamine to afford the stable intermediate 6-amino-N1-methoxy-2-(N,N-dimethylamino) 197 via 196. A DR was accomplished by heating in the presence of a dimethylammonium hydrohalide salt to give the 6-N-methoxy nucleosides 198 in high yield. In the absence of heating, 197 did not rearrange. The rearrangement can be carried out without isolation of 197 simply by refluxing in methanol (Scheme 57) (98JOC3213). When tricyclic 199 was stored in an aqueous solution at neutral pH it rearranged to 201 by a ring opening of 199 to yield an N1-propanal

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203

Scheme 56

Scheme 57

adduct 200, which underwent the DR to the N6-propanal adduct 201

(Scheme 58) (68B3453, 73JOC2247, 88MI275, 99CG2025, 06CRT571). The

N1-deoxyadenosine adducts 202 underwent a DR to N6 adducts 203

(Scheme 59) (02CRT1572).

204

El Sayed H. El Ashry et al.

Scheme 58

Scheme 59

N-labeled adenosine [6-15N] 204 and deoxyadenosine generated the N adduct with 205 to form 206, which hydrolyzed to 207. The N1 adduct of 207 was isomerized to its N6 derivatives 210 at pH 13 through a DR involving ring opening to 208 and recyclization to 209, which dehydrates to 210 (Scheme 60) (98H359, 99JA6773, 01JA11126). N,N-bis(2-chloroethyl)-p-aminophenylbutyric acid 212 (chlorambucil) reacts with deoxyadenosine 211 in a non-nucleophilic buffer (0.2M cacodylic acid, 50% base) at 37C to give 213 that rearranged to 214 when treated with aqueous base. Although the rearrangement under basic con­ ditions was quantitative, the rate was slow (90CRT587) and under neutral conditions still slower (Scheme 61) (03CRT403). The DR of 215 gave 216 whose purification on ion-exchange chroma­ tography afforded triethylammonium salt 217 in 70% yield (Scheme 62) (01JA8750). Hydrolytic cleavage of 1-alkoxy-7-alkyladenines 218 produced imida­ zol-5-carboxyamidines 219 in 53—60% yields then followed by a DR to give N6-alkoxy-7-alkyladenine 220 (Scheme 63) (97CPB832). Oxidation of N6-benzyladenine (R = Bn) 221 afforded the N1-oxides 222 whose structure was established by conversion to N6-methoxyade­ nine 225 through O-methylated 223 followed by a DR to 224 and then a non-reductive debenzylation (Scheme 64) (96CPB967). 1-Benzyladenine-7-oxide 226 was converted by a DR to N6-benzyla­ denine-7-oxide 227 on heating with alkali (Scheme 65) (95CPB325). 15

6

Recent Advances in the Dimroth Rearrangement

205

Scheme 60

Scheme 61

DR isomerization of [N1-methyl-50 -deoxyadenosylcobaltamine]Cl 228

in water and ethylene glycol gave N6-methyl-deoxyadenosylcobaltamine

229 (Scheme 66) (97CB373, 98JIB45).

206

El Sayed H. El Ashry et al.

Scheme 62

Scheme 63

Scheme 64

The DR was implemented with dimethylsulfate-modified RNA to explore which position was modified within Escherichia coli ribosomes. Selective DR of a 1-methyladenosine adduct could provide a means to

Recent Advances in the Dimroth Rearrangement

207

Scheme 65

Scheme 66

distinguish between the different methylated derivatives 230 and 232. Both modifications resulted in opening of the six-membered ring at neutral to slightly alkaline pHs. This process was quite slow for 1-methyladenosine at neutral pH, but at pH 9 and 25C it occurred with a 1-day half-life and once the ring was opened, it rapidly underwent a DR to produce the highly stable 6-methyladenosine 231 (Scheme 67). The N3-methylated 232 adduct also underwent a ring opening to form the N-methylformamido-imidazole 233 at neutral to alkaline pH, but it recy­ clized back to 3-methyladenosine 232. These results offer an approach to determine which nitrogen of a given adenosine was methylated within an RNA sequence because mild base treatment of modified RNA can result in migration of methyl groups from N1 to N6 (01RNA1403). Modified oligonucleotides also easily undergo a DR (07HCA928). When purines 234 and ethanolamine (2.5 molar equivalent) were heated under reflux in methanol containing a catalytic amount of DBU, a mixture of DR isomers pyrimido[5,4-d]pyrimidines 237 and 238 in a 1:2 ratio was obtained. Also, 235 gave 237 (Scheme 68) (07EJO1324).

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El Sayed H. El Ashry et al.

Scheme 67

Scheme 68

Similarily, 236 was converted to a mixture of 237 and 238 in 1:4 ratio. The transformation of 238 into 237 arises by a DR. A nucleophile caused ring opening of the pyrimidine ring in 238 that has an exocyclic double bond, and subsequent ring-closure afforded the more stable 237.

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209

Scheme 69

Structure 238 arises from nucleophilic attack of ethanolamine on C8 of purine 236 followed by ring opening and ring closure (Scheme 68) (07EJO1324). A divergent synthesis of substituted 2-aminoimidazoles 240 starts from 2-aminopyrimidines and a-bromocarbonyl compounds. Conven­ tional heating or microwave irradiation affords 2-hydroxy-2,3-dihydro­ 1H-imidazo[1,2-a]pyrimidin-4-ium salts 239. Their hydrazinolysis gave 2-amino-1H-imidazoles 240 via a DR (Scheme 69) (08JOC6691).

3.2.6 Pyranopyrimidines

The functionalized azolopyrano-pyrimidine 241 was converted to 242 under basic conditions via a DR (Scheme 70) (98MOL71).

3.2.7 Pyridopyrimidines

Pyrido[2,3-d]pyrimidines 245 are prepared directly by amination of 243 with amines at 140C whereas at room temperature imine 244 forms. But subsequent heating with the same reagent gives 245 via a DR (Scheme 71) (06EJM1011). 6-Amino-4-(4-methoxyphenyl)-2-thioxo-1,2-dihydropyridine-3,5-dicar­ bonitril 246 and phenyl isothiocyanate in pyridine gave 2,7-dimercapto-5­ (4-methoxyphenyl)-4-phenylaminopyrido[2,3-d]pyrimidine 247 as a result of a DR (Scheme 72) (05JS381).

Scheme 70

210

El Sayed H. El Ashry et al.

Scheme 71

Scheme 72

3.2.8 Quinazolines

Quinazoline 250 began as amino nitrile 248 by conversion to 249 and then reaction with 3-chloro-4-fluoroaniline via cyclization and then a DR (Scheme 73) (01OPD581, 07OPD813). Similarly, amino nitrile 251 was treated with DMF—DMA in toluene to yield formamidine 252 that was reacted with 3-ethynylaniline to give 253 by a DR (Scheme 74) (07OPD813). Amino nitrile 254 with 255 led to the selenourea 256, which underwent a ring closure to give 257 (Scheme 75) (04HCA1873). An isomerization via ring opening to 258 and ring closing led to 259 via a DR (97CPB832, 98H359). Iminoquinazoline 260 (R1 = CH3, R2 = H, R3 = CH2Ph) in 1 M sodium hydroxide yielded 4-alkylaminoquinazoline 261 (Scheme 76) (05T5778). Iminoquinazolines 262 readily underwent a DR under basic condi­ tions to quinazolines 263 (Scheme 77) (06JME955).

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211

Scheme 73

Scheme 74

Iminoquinazolines 265 from 264 underwent a DR to afford 1-(2­ phenylquinazolin-4-yl)-3-substituted thioureas 266. The tautomerization of 266 involving the proton of the N1 substituted thioureas and N3 of the quinazoline ring gave either 267 or 268, stabilized by hydrogen bond interactions (Scheme 78) (01MOL574, 01MOL588). Attack of the amino group in 270 onto the isothiocyanate group in 269 gave 271 that cyclized to 272. Subsequent attack of the imino nitro­ gen onto the carbonyl group afforded 273. A DR did not take place (Scheme 79) (07T11287).

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Scheme 75

Scheme 76

Scheme 77

3.2.9 Thiazines

A library of functionalized 2-amino-1,3-thiazines 274 was reported (04AGE621, 05QC364). They underwent a thermal uncatalyzed DR to the thermodynamically more stable pyrimidine-2-thiones 275 (75M1469, 06QC509) under microwave irradiation in a batch or continuous flow

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213

Scheme 78

format, employing either toluene or 1-methyl-2-pyrrolidone solvent. Thiazines bearing an ester group at the C5 position rearranged at a considerably higher temperature than derivatives without substituents at this position. This thermal rearrangement was studied in detail using differential scanning calorimetry and density functional theory computa­ tional methods. The reaction pathway involved a zwitterionic intermedi­ ate (06QC509). The optimized conditions involved heating 274 in toluene together with a silicon carbide at 220C for 30 min to provide a 68% yield (Scheme 80) (06JOC4651).

3.2.10 Benzo and Pyrido-oxazines

A one-pot three-component synthesis of benzo[1,3]oxazine 280 (X = H) from 2-hydroxybenzonitril 276 with 1,10 -carbonyldiimidazole and hydro­ xylamine gave 278 via 277. Cyclization of 278 with triethylamine gave benzo[4,3]oxazine 279, which readily rearranged under basic conditions via a DR to 4-methoxy (aralkoxy)iminobenzo[1,3]oxazine-2-ones 280 (Scheme 81) (04S1987). Similarly, 2-cyano-3-hydroxy-pyridine 276 (X = N) was converted to 280 (X = N) (Scheme 81) (05T3091). Amino nitrile 281 with formic acid gave the DR product spiro{6H-indeno [20 ,10 :5,6]pyrano[2,3-d]pyrimidine-5,30 -indoline} 283 via 282. The same

214

El Sayed H. El Ashry et al.

Scheme 79

Scheme 80

281 with an acetic anhydride/pyridine mixture afforded 10 ,2-dimethyl­ spiro{6H-indeno[20 ,10 : 5:6]pyrano[2,3-d]pyrimidine-5,30 -indoline}-20 , 2, 6 (3H)-trione 284 via a DR (Scheme 81) (08H955).

3.2.11 Thiazolidines The DR of the thiazolidine ring into the imidazolidine ring occurs under basic conditions. Alkylation of 285 with diiodomethane containing sodium hydride gave imidazolidino[1,5-a]piprazin-4-one 287 via 286. The imidazolidino[1,5-a]perhydroquinoxalin-4-one 289 was similarly pre­ pared from 288 via a DR of the intermediate thiazolidines (Scheme 82) (04S2169).

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Scheme 81

215

216

El Sayed H. El Ashry et al.

Scheme 82

3.2.12 Imidazolidines

When 290 was heated in the presence of a base such as triethylamine it furnished 4-alkoxy(aralkoxy)-iminoimidazolidin-2-ones 292 by a base­ catalyzed DR of the cyclized 291 (Scheme 83) (04T2409).

3.2.13 Oxazolidines

Successive treatment of cyanohydrins with 1,10 -carbonyldiimidazole and O-substituted hydroxylamines furnished 293, which with Et3N under­ went a DR to 294 in 70—80% yield (Scheme 84) (04OBC2023, 04S1340). The reaction of 295 with equimolar amounts of sodium methoxide in boiling methanol furnished the rearranged 296 in 51—72% yields (Scheme 85) (06S1803). Thermal reaction of pyridoimidazole heterocumulenes 297 yielded, via a DR intermediate, the pyridoimidazole-linked imidazoledione 298 (Scheme 86) (97JOC4085).

Scheme 83

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217

Scheme 84

Scheme 85

Scheme 86

3.3 Heterocycles with three heteroatoms in the ring 3.3.1 Triazoles

The azidosulfonylcalixarene 300 was obtained in 55% yield from chlor­ osulfonylcalix[4]arene 299 (cone conformation) with sodium azide. Their cycloaddition to N-phenyl- and N-cyclohexyl-2-cyanoacetamides in the presence of EtONa gave the tetrakis((1H-1,2,3-triazol-5-amine)sulfonyl) calix[4]arenes 302 in 38—60% via 301. A simple analog was prepared from tosyl azide 302 with N-phenyl-2-cyanoacetamide 304 to give the DR product, 1H-5-tosylamino-1,2,3-triazole-4-N-phenylcarboxamide 305 (Scheme 87) (04ARK31).

218

El Sayed H. El Ashry et al.

Scheme 87

3.3.2 Thiadiazoles

5-Halo-1,2,3-thiadiazoles 306, having at the 4-position an electron-with­ drawing group, with amines gave 307, which were not isolated but immediately reacted with a second equivalent of 5-chlorothiadiazoles 306 to afford 310 via 309 (84JHC627, 89JHC1811, 94KGS554). The 1,2,3­ thiadiazole rings of 310 underwent DR to dithiols 311 (Scheme 88) (99CC2273). The ester group in triazole 308 (R1 = CO2Et) was unstable in acid (pH > 1) and caused a partial reverse DR, whereas 308 (R1 = CONH2, CONHCH3) with amide groups were stable even in a

Recent Advances in the Dimroth Rearrangement

219

Scheme 88

strong acidic medium. 1-(o-Aminophenyl)-1,2,3-triazolo-5-thiols 308 was obtained via a DR by heating 5-arylamino-1,2,3-thiazoles 307 (R = COOEt, CONHMe, CONH2) in ethanol in the presence of triethylamine, followed by acidification (04RJOC870). Similarily, 306 with aliphatic diamines gave bisthiols 313 via 312. Hydrogen sulfide was lost from dithiols 313 by an intramolecular nucleophilic substitution, yielding thiadiazepines 314 (Scheme 89) (99CC2273).

3.3.3 Oxadiazoles The cycloaddition of 4-amino-3-azido-1,2,5-oxadiazole to nitriles with activated methylene groups gave 3-amino-4-(5-amino-1H-1,2,3-triazol-1­ yl)-1,2,5-oxadiazoles whose DR gave N-(4-R-1H-1,2,3-triazol-5-yl)-1,2,5­ oxadiazole-3,4-diamines (04MC76).

3.3.4 Selenadiazines

When selenadiazines 315 was subjected to acid hydrolysis at 100C a ring contraction occurred to form 316, which underwent a DR to form 4-aryl-1-methyl-5-selenoxo-1,2,4-triazole-3-carboxamide 317 (Scheme 90) (08ZN415).

220

El Sayed H. El Ashry et al.

Scheme 89

Scheme 90

3.4 Heterocycles with four heteroatoms in the ring 3.4.1 Tetrazoles

Thermal isomerization of 1,5-diaminotetrazole 318 to tetrazolohydrazine 319 took place via a DR (90CB1575). The possibility of rearrangement of 318 caused the participation of its isomeric structures during the reaction with 1,3-diphenylpropenone 320 to give three isomeric products, the seven-membered triazepines 321 and 322 in addition to 1-(5-tetrazolyl)­ 3,5-diaryl-D2-pyrazolines 323 (Scheme 91) (06JST114). Fusion of 5-chloro-1-phenyl-1H-tetrazole 324 with 4-methoxyaniline gave N-[1-(4-Methoxyphenyl)-1H-tetrazol-5-yl]aniline 325. X-ray crystallographic diffraction analysis showed that, as a result of a DR, structure 325 was correct and it is not that expected of a simple substitution of chlorine in 5-chloro-1-phenyl-1H-tetrazole by aniline (Scheme 92) (01JCS(P2)1315).

Recent Advances in the Dimroth Rearrangement

Scheme 91

Scheme 92

221

222

El Sayed H. El Ashry et al.

ACKNOWLEDGMENTS Thanks are due to Prof. V. Whittmann for his valuable help. Support from AvH in Germany and the Higher Education Commission in Pakistan are highly appreciated. Encourgement, valuable comments, and invitation to write a chapter in this volume by Prof. A. Katritzky are highly appreciated.

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84JHC627 88BCG867 88MI275 89JHC1811 90CB1575 90CRT587 92JBC23427 92MI35 94CG1903 94JA7481 94JAM339

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El Sayed H. El Ashry et al.

99IARC123 99JA1958 99JA6773 99JCS(P1)1333 99JOC365 99JOC634 99JOC1778 99JOC9493 99OL1233 00B924 00CBI201 00CRT18 00CRT421 00CRT625 00EMM48 00JAM24 00JME2196 00JOC205 00JOC2827 01B9780 01CBI111 01CEJ2617 01CL738 01JA8750 01JA11126 01JCS(P2)1315 01JOC6576 01MOL574 01MOL588

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Recent Advances in the Dimroth Rearrangement

01OPD581 01RNA1403 01SL1437 01T8305 02CRT1549 02CRT1572 02H631 03ACR899 03CRT403 03CRT1328

03MOL467 04ARK31 04AGE621 04CRT717

04CRT950 04CRT1007

04CRT1531 04CRT1638 04CRV4125 04EJO1897 04HCA1873 04JOC8148 04MC76 04MI379 04OBC2023 04PNA14051 04RJOC85 04RJOC870 04S1340 04S1987 04S2169

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226

04SL2779 04T2409 04TL8007 05ACSV429 05B3327

05CAB237 05CC3968 05CRT145

05H2683 05HAC226 05JA3692 05JAM1713 05JME5728

05JMP1417 05EJOC2914 05JOC6034 05JS381 05QC364 05RCB719 05T3091 05T5778 06CRT571 06CRV607 06EJM1011 06JAM1335 06JME955

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Recent Advances in the Dimroth Rearrangement

06JST114 06JOC4651 06M1543 06OPD398 06QC509

06RCB1492 06RCB2247 06RJO1403 06S1803 07ARK92 07BML1376

07CB299 07CRT790 07EJO1324 07H619 07HCA928

07HTC405 07OPD813 07T11287 07TL2041 08CRT1163 08H777 08H955 08H1479 08H2421

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08JCR334 08JOC6691 08T1101 08T10339 08TL5125 08ZN415 09AC183

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SUBJECT INDEX Acetylated glycosamino acid, 57 Acid catalysis in Dimroth rearrangements, 164 2-Acylindole, reaction with an arylhydrazone, 100 Addition of electrophile ring opening, ring closing processes, 162 Addition of nucleophile ring opening, ring closing processes, 162 Adenine, Dimroth rearrangement, 199 Adenosine, Dimroth rearrangement, 190 bisAlkene-modified bisterpyridine monomers, self-assembly, 51 N6-Alkoxy-7-alkyladenine, 204 1-Alkoxy-7-alkyladenines, hydrolytic cleavage, 204 3-(�-Alkoxyalkyl)benzofurans, 78 4-Alkoxy(aralkoxy)-iminoimidazolidin-2­ ones, by Dimroth rearrangements, 216 N1-Alkyladenines, Dimroth rearrangements, 201 5-Alkylidene-2,5-dihydropyrrol-2-one, 184 5-Alkylidene-5H-pyrrolin-2-ones, 185 2-Alkyl-2-imidazolines, reaction with �,�-unsaturated aldehydes & ketones, 138 reaction with diethylacetylene dicarboxylate, 140 reaction with ethyl acetoacetate, ethyl benzoylacetate, and ethyl 2-oxocyclohexanecarboxylate, 139 reaction with methyl propynoate, 139 o-Alkylphenyl carbamates, cyclization, 83 o-Alkylphenyl ureas, cyclization, 83 o-Alkynylallyloxybenzenes, intramolecular carbo-alkoxylation, 77 2-Alkynylanilines, cyclization, 98 o-Alkynyl aryl amides, platinum-catalyzed cyclization, 83 o-Alkynylphenyl acetals, PtCl2-catalyzed cyclizations, 78 o-(-Alkynyl) phenyl ethers, cyclization, 77 (o-Alkynylphenylthio)silanes, gold-catalyzed cyclization, 90

o-Alkynyltrifluoroacetanilides, reaction with palladium complexes, 83 3-Allylbenzofurans, 77 Allyl tosylamides, gold-catalyzed cyclization, 88 Amidine rearrangement, 162 2-Amidotoluene, Madelung cyclization, 98 3-Amino-4-(5-amino-1H-1,2,3-triazol-1-yl)­ 1,2,5-oxadiazoles, Dimroth rearrangement, 219 4-Amino-3-azido-1,2,5-oxadiazole, cycloaddition to nitriles, 219 2-R-Amino-5,7-di-methyl[1,2,4]triazolo­ [1,5-a]pyrimidines, 172 2-Aminoethylpyridine, reaction with 2-phenyl-4-formylimidazole, 60 3-Amino-4-imino 7H-pyrrolo[3,2-e][1,2,4]­ triazolo[1,5-c]pyrimidine, 193 6-Amino-4-(4-methoxyphenyl)-2-thioxo­ 1,2-dihydropyridine-3,5­ dicarbonitrile, reaction with phenyl isothiocyanate, 209 6-Amino-3-methyl-5-(N-2-hydroxypropyl)­ iminomethyl)-1-(4-nitrophenyl) uracil, 192 7-Amino-4-[(4-methylphenyl)amino]­ pyrido-thieno[3,2-d]pyrimidine-8­ carbonitriles, 194 6-Amino-4-oxopyrano[3,4-d][1,2,3]­ thiadiazoles, Dimroth rearrangements, 188 1,4-bis-(20 -Aminophenyl)but-1,3-diyne, gold(III)-catalyzed cyclization, 98 1-(o-Aminophenyl)-1,2,3-triazolo-5-thiols, by Dimroth rearrangements, 219 2-Aminopyrimidines, reaction with ethyl bromoacetate, 190

reaction with �-bromocarbonyl

compounds, 209 Aplidiamine, 201 3-Arylacetylindoles, nitration, 102 4-Aryl(alkyl)-1-(4,6-dimethylpyrimidin-2­ yl)thiosemicarbazides, reaction with methyl iodide, 172

229

230

Subject Index

4-Aryl-1-methyl-5-selenoxo-1,2,4-triazole­ 3-carboxamide, formation by Dimroth

rearrangement, 219

6-Aryl-1,2,4-triazin-3(2H)-ones, heating

with carboxylic acid hydrazides, 180

3-Aryl-7-(trifluoromethyl)imidazo[1,2-a]­ pyrimidine, 171

2-Aryl-7-(trifluoromethyl)imidazo[1,2-a]­ pyrimidine, by Dimroth

rearrangement, 171

Azidosulfonylcalixarenes, by Dimroth

rearrangement, 217

Azolopyrano-pyrimidines, 209

Azomethine ylides, 140

Bacteriochlorophylls, 14

Benzo[b]carbazoles, 102

Benzo[1,3]oxazines, 213

Benzo[4,3]oxazines, Dimroth

rearrangements, 213

N6-Benzyladenine, oxidation, 204

1-Benzyladenine-7-oxide, Dimroth

rearrangement, 204

N6-Benzyladenine-7-oxide, 204

2-Benzylamino-1-phenylethanamine, 151

N-Benzyl-1,2-diaminoethane, cyclization to

imidazolines, 128

reaction with triethyl orthoformate, 141

1-Benzyl-2-(ethoxycarbonylmethylene)­ 1,2,3,4-tetrahydroimidazole, 129

[3þ3] annulations, 134

mono and di-alkylation, 131

reaction with conjugated aldehydes,

133

reaction with diethyl oxalate, 137

reaction with dihaloalkanes, 132

reaction with ethyl propenoate, 134

reaction with �-keto-esters and 1,3­ diesters, 136

1-Benzyl-2-imidazoline, 129

alkylation with active halide, 141

reaction with dimethyl fumarate, 148

reaction with ethyl 5-(bromoacetoxy)­ pent-2-enoate, 144

reaction with fumaronitrile, 149

2-Benzyl-2-imidazoline, double

deprotonation, 128

reaction with but-3-en-2-one, 138

reaction with methyl propenoate, 139

reaction with �-keto esters to

regioisomeric imidazopyridin-7-ones,

140

2-Benzylimidazolines, reaction with

N-phenylmaleimides, 147

1-Benzyl-2-methyl-2-imidazoline, 128

C-alkylation followed by removal of

benzyl group, 130

1-Benzyl-2-methyl-3a,4,7,7a-tetrahydro­ 1H-benzimidazole, C-2(�)

metallation, 131

1-Benzyl-4-phenyl-2-imidazoline, 151

in alkylation-deprotonation sequence,

152

enantiomerically pure, 151

enantiomers, reaction with alkylating

agent and dipolarophile, 155

Bicyclic heterocumulenes, rearrangement

to yield imidazole-dione ring via an

oxazole, 166

2,20 -Biindole, Diels-Alder addition of

maleimides, 116

2,20 -Biindolyl, 98

heating with 4-dimethylamino-1,1,1­ trifluoro-3-buten-2-one and triflic

anhydride, 119

3,30 -Biindolyl, 110

reaction with dimethyl

acetylenedicarboxylate, 117

2,20 -Biindolyl-7,70 -dicarbaldehyde, 105

Biindolyls, 97

2,30 -Biindolyls, 102, 106

3,40 -Biindolyls, 110

3,70 -Biindolyls, 102, 110, 118

4,40 -Biindolyls, 110

4,70 -Biindolyls, 110

7,70 -Biindolyls, 110

2,50 -Biindolyls, by double Fischer

syntheses, 100

3,50 -Biindolyls, by double Fischer

syntheses, 100

5,50 -Biindolyls, by double Fischer

syntheses, 100

4,40 -Bimethyl-2,20 -bipyridine, mono­ lithiation, 39

Bipyridine-based hexameric architectures,

36

2,20 -Bipyridine-based macrocycles, 36

Bipyridine benzyl ether dendron, 25

tris-2,20 -Bipyridine ligands, self-assembley

with Fe(II), 39

4,40 -Bipyridine, in macrocycles, 25

Bismuth-catalyzed carbo-oxycarbonylation

of alkynyl esters, 83

�-Branched 2-alkyl-2-imidazolines, 129

Subject Index

3-Bromo-8-(p-anisyl)-1,10-phenanthroline, 59 Bromoaryl bisterpyridine ligand, 43 3-Bromobenzaldehyde, reaction with 2-acetylpyridine, 51 1-Bromo-4-dibromomethylimidazo[1,2-a]­ pyridine, rearrangement to 2-bromo­ 4-formyl isomer, 169 3-Bromoindole, reaction with indole, 106 1-Bromo-3-iodobenzene, 22 3-(p-Bromophenyl)-4,6-dimethoxyindole, reaction with 2-indolinone and phosphoryl chloride, 107 4-(3-Bromophenyl)-pyrimidine, reaction with (3-bromophenyl) lithium, 53 40 -(3-Bromophenyl)-2,20 :60 ,200 -terpyridine, 50 Bromoterpyridines, reaction with an iodomonoterpyridineRu(III) adducts, 53 n-Butyloctahydroacridine, 33 2-t-Butyloxycarbonyl-4­ methoxycarbonylpyrrolidine, 154 N-tert-Butyloxycarbonyl-2-methyl-2­ imidazoline, 129 N,N0 -bis(3-tert-Butyl-5-(4-pyridyl) salicylidene)-1,2-diamino­ cyclohexane, in zinc complexes, 28 Calix[6]furan, synthesis and metal binding, 3

conversion to calix[6]pyrroles, 7

reduction, 4

Calix[6]pyrroles, 6 complexes with iodine, 8 Calix[4]pyrroles, selectivity for fluoride ions, 8 4-Carboethoxy-5-arylamino-1,2,3-thiazoles, Dimroth rearrangement, 219 4-Carboethoxy-5-chloro-1,2,3-thiazoles, reaction with ethylenediamine, 219 N,N0 -Carbonyl-bis-indoles, intramolecular palladium catalysed coupling, 110 N-[N0 -(Carboxymethyl)benzimidazol-2-yl­ methyl]-N,N-bis(benzimidazol-2­ ylmethyl)amine, in copper macrocycles, 21 Chiral bis(pinene-2,20 -bipyridine) ligands, 40 2-Chloroacetophenone, conversion into tert-butyl oxime ether, 156

231

N,N-bis(2-Chloroethyl)-p­ aminophenylbutyric acid, reaction with deoxyadenosine, 204 4-(30 -Chloro-40 -fluorophenyl)-6-(30 ­ morpholinopropoxy)-7­ methoxyquinazoline, 210 2-Chloro-3-methylindole, combined with 3-methylindole, 105 4-(3-Chlorophenylamino)-5,6-dimethyl­ 7H-pyrolo-[2,3-d]pyrimidine, 193 7-Chloro-4-phenylamino[1,2,4]triazolo­ [4,3-a]quinazolin-5(4H)-ones, 180 3-(3-Chlorophenyl)-5,6-dimethyl-4H­ pyrrolo[2,3-d]pyrimidine-4-imine, 193 5-Chloro-1-phenyl-1H-tetrazole, fusion with 4-methoxyaniline, 220 reaction with aniline, 220 2-Chloropropenonitrile, as an alkyne equivalent dipolarophile, 143 Chlorosulfonylcalix[4]arene, reaction with sodium azide, 217 Chromium carbene complexes of 2,20 ­ biindolyls, conversion to indolocarbazoles, 117 Clonidine, 126 18-Crown-6 ethers, 3 18-Crown-6 skeleton, 21 Cucurbituril, 18 Cyanohydrins, reaction with 1,10 -carbonyldiimidazole and O-substituted hydroxylamines, 216 2-Cyano-3-hydroxy-pyridine, 213 1-Cyanoisoindole, 87 6-Cyano-7-phenyl-1,2,4-triazole[4,3-a]­ pyrimidin-5(8H)-one, 173 Cyclic 2-acylindole, reaction with phenylhydrazine, 101 Cyclic hexameric macrocycle containing three Sn(IV) porphyrins, 11 Cyclic hexamers, containing six porphyrins bridged by diphenylethynes, 13 containing pyrimidine-type ligands, 53 Cyclic hexa-�-peptides, 57 Cyclic maltooligosaccharides, 56 Cyclic oligosaccharides with �-(2!1) linked-D-fructofuranose units, 19 Cyclic porphyrin-trimer with octatetrayne bridges, 11 Cyclodextrin glycosyl transferases, 56 Cyclodextrins, 56

232

Subject Index

Cyclofructans, 19

Cyclohexathiophenes, 5

4-Cyclohexyl-1-substituted 1,2,4-triazolo­ [4,3-a]quinazolin-5-(4H)-ones, Dimroth rearrangements, 180

Cycloinuloheptaose, 21

Cycloinulohexaose, 21

Cycloinulooctaose, 21

Cyclol, 134

Cyclo[7]pyrrole, 8

Cyclo[8]pyrrole, 8

Cyclo[6]pyrroles, 6

synthesis, 8

Cyclo-20 :40 ,400 :200 ,2000 :4000 ,40000 :20000 ,200000 :400000 ,

4-sexipyridine, 40

Cyclotetrathiophene, 5

[3-15N,4-15NH2]Cytidine, synthesis, 192

2-Deoxyadenosine, reaction with recemic

(1-chloroethenyl)oxirane, 199

Deoxyadenosyl-N6- triol, in Chinese

hamster ovary cells, 199

D6h porphyrin[6]nanoring, 16

1,5-Diaminotetrazole, thermal

isomerisation to tetrazolohydrazine, 220

3,30 -Diarylamino-2,20 -biindolyls, 99

Diazakekulene, 31

Dibenzylideneheptacycle, 33

2,20 -Dibromo-4,40 -bipyridine, 40

5,50 -Dibromo-2,20 -bipyridine, 36

Sonogashira coupling of alkyne moieties, 41

4,40 -Dibromomethyl-2,20 -bipyridine, 39

2,6-Dibromopyridine, Pd-catalyzed aryl

amination with 2,6-bis(methylamino)­ pyridine, 36

3,5-Dibromopyridine, Sonogashira-

Hagihara cross-coupling reaction with

2-methyl-3-butyn-2-ol, 22

3,30 -Diethyl-4,40 -dimethyldipyrromethane,

reaction with 3-ethynylbenzaldehyde,

9

1,3-Diethynylbenzene, condensation

with 3-bromobenzaldehyde, followed

by acidic condensation with pyrrole,

18

2,6-Diethynylpyridine, in complexes, 22

3,5-Diethynylpyridine, Pd-catalyzed cross­ coupling with dimethyl substituted

vinyl triflate, 23

3,4-Difluoro-1H-pyrrole, reaction with acetone, 7

3,30 -Diformyl-1,1-biindolyl, 114

9,10-Dihydrophenanthrene, acylation with

succinic anhydride, 31

5,6-Dihydro-N-phenyl-2-(phenylimino)­ 2H-thiopyran-4-amine, 190

5,6-Dihydroxyindole-2-carboxylic acid,

oxidative dimerisation, 115

5,6-Dihydroxyindoles, oxidation, 115

5,6-Dihydroxy-2-methylindole, oxidative

dimerisation, 115

Diindolyl succinic anhydride, photolysis,

110

1,4-Diiodobenzene, reaction with ethynyl-

substituted terpyridine, 51

Dilithiated 4-(phenylimino)pentan-2-one,

184

2,7-Dimercapto-5-(4-methoxyphenyl)-4­ phenylaminopyrido[2,3-d]pyrimidine,

209

Dimethanoglycoluril, cyclic hexamer, 18

4,6-Dimethoxy-3-arylindoles, 102

4,6-Dimethoxy-2,3-diphenylindole,

reaction with 2-indolinone and

phosphoryl chloride, 107

4,6-Dimethoxy-3-methylindole, reaction

with hydrogen chloride gas, 105

4,6-Dimethoxy-2-phenylindole, reaction

with 2-indolinone and phosphoryl

chloride, 107

6,60 -Dimethyl-2,20 -bipyridine, oxidation, 30

4,6-Dimethyl-2-hydroxypyridine, 53

Dimethylindol-2-ylborates, in palladium-

catalyzed homocoupling reactions,

109

10 ,2-Dimethylspiro{6H-indeno[20 ,10 : 5,6]­ pyrano[2,3-d]pyrimidine-5,30 ­ indoline}-20 ,2,6(3H)-trione, 214

Dimethyl substituted vinyl triflate, Pd­ catalyzed cross-coupling with 3,5­ diethynylpyridine, 23

Dimroth rearrangement, 162

2,4-Dinitrophenoxyamine, reaction

with diacetyl-5-methyl-deoxycytidine,

178

Dinuclear 4,40 -di-t-butyl-2,20 -bipyridine Re (I) tricarbonyl complexes, 22

Dioxopyrrolo[1,2-a]imidazole, 137

Subject Index

2,3-Diphenyl-4,6-dimethoxyindole,

acetylation, 102

oxidative dimerisation, 112

reaction with 3-methyl-2-indolinone and

phosphoryl chloride, 108

reaction with 4,6-dimethoxy-2­ indolinone and phosphoryl chloride,

108

reaction with 4,6-dimethoxy-3­ spirodithiolan-2-indolinone and

phosphoryl chloride, 108

1,3-Diphenyl-4-hydrazino-pyrazolo[3,4-d]­ pyrimidine, 175

N-(1,3-Diphenylpyrazolo[3,4-d]pyrimidin­ 4-yl)hydrazones, 175

5,10-Diphenyltripyrrane, 6

Dipyrrins, 18

Dipyrrolemethane, reaction with simple

ketones, 7

2,3-Disubstituted benzo[b]selenophenes, 91

2,3-Disubstituted benzothiophenes, 89

2,20 -Dithiomethyl-3,30 -biindolyl, 112

DNA, treated in vitro with styrene oxide,

196

Dodecafluorocalix[6]pyrrole, 7

Dodecahydro-18,21-dioxoniakekulene, 30

Dodecahydro-19,20,21,22,23,24-hexaaza­ kekulene, 33

Dodecahydro-19,20,22,23-tetraaza-21,24­ dioxoniakekulene, 33

Electrospray mass spectrometry, of copper

metallocenes, 56

Energy- and electron-transfer devices, 38

Erypoegin H, 81

2-Ethoxymethyleneamino-1H-pyrrole-3­ carbonitrile, reaction with hydrazine

hydrate, 193

Ethyl 5-amino-3-methylimidazo[1,2-c]­ pyrimidine-2-carboxylate, 171

Ethyl 5-amino-2-methylimidazo[1,2-c]­ pyrimidine-3-carboxylate, hydrolysis,

171

2-Ethyl-4-benzylamino-6-nitroquinazoline,

210

Ethyl 5-(bromoacetoxy)pent-2-enoate,

reaction with 1-benzyl-2-Imidazoline,

144

Ethyl N-4-cyano-1-(4-substituted)-1H­ pyrazol-5-ylformimidate, reaction

with monosubstituted hydrazines, 194

233

Ethyl diazoacetate and fumarate esters,

addition to 1-benzyl(methyl)-2­ imidazoline, 146

(R)-2-Ethylpiperidine, 152

3-Ethynylbenzaldehyde, reaction with 3,30 ­ diethyl-4,40 -dimethyldipyrromethane,

9

o-Ethynylbenzyl �-aminophosponates,

cyclization to isoindoles, 88

bis(4-Ethynylphenyl)porphyrin, reaction

with metal-free bis(3-iodophenyl)­ porphyrin, 13

Ferrocene-1-carboxylic acid, reaction with

3,5-bis(pyridin-4-ylethynyl)phenol,

25

tris(Ferrocene) hexamer, 26

Fluoro hexameric metallocrowns, 63

Free-base porphyrin-trimer, 16

Fully unsaturated azakekulene, 31

Functionalized 2-amino-1,3-thiazines,

Dimroth rearrangement, 212

Functionalized-pyrimid-2(1H)-thiones, 212

Gable-porphyrins, in macrocycles, 15

Glycoluril, reaction with excess

formaldehyde, 18

Gold-catalyzed intramolecular

aminosulfonylation, 86

Gold-catalyzed intramolecular

carbothiolation of alkynes, 89

1-(Guan-7-yl)-4-(aden-1-yl)-2,3-butanediol,

201

5-Halo-1,2,3-thiadiazoles, reaction with

amines, 218

Helicates, 39

Hemicucurbituril, 19

meso-(n-Heptyl)dipyrromethane, reaction

with isophthalaldehyde and 1-methyl­ 2-imidazolecarbaldehyde, 15

Heterokekulenes, 30

Hexaazakekulene, 31

3,9,15,19,21,23-Hexaazakekulene, 34

Hexahydropyrrolo[1,2-a]imidazoles,

optically active, 153

Hexahydropyrrolo[1,2-a]pyrazines, 145

Hexakis(ferrocene) hexamer, 26

Hexameric �-cyclodextrin, 56

Hexameric macrocycle containing six furan

rings joined via acetylene bridges, 4

234

Subject Index

Hexameric macrocycles, composed of six

5,50 m-phenylene-bridged

imidazolylporphyrinatozinc(II)

dimers, 14

Hexameric macrocycles possessing

subunits with oxygen, 3

Hexameric porphyrin-trimer, 9

Hexameric trisbipyridine, 41

N,N0 ,N00 ,N000 ,N0000 ,N00000 -Hexamethylazacalix­ [6](2,6)pyridine, 34

meso-Hexa(pentafluorophenyl)hexaphyrin,

7

meso-Hexaphenylhexaphyrin, 6

Hexaphyrins, 6

Hexaruthenium macrocycles, 42

o-Hexyl-3,5-bis(terpyridine)phenol ligand, 45

reaction with ruthenium compounds, 46

Homofascaplysin C, 101

4-Hydrazino-2-methylthio-thieno[2,3-d]­ primidines, cyclization with one

carbon-inserting agent, 174

4-Hydrazinoquinazoline, reaction with

�-ketocarboxylic acids, 181

2-(2-Hydroxyalkyl)-2-imidazolines, 136

2-Hydroxybenzonitrile, reaction with 1,10­ carbonyldiimidazole and

hydroxylamine, 213

N1-(1-Hydroxy-3-buten-2-yl)-20­ deoxyadenosine adducts, 196

2-Hydroxy-2,3-dihydro-1H-imidazo[1,2-a]­ pyrimidin-4-ium salts, formation and

Dimroth rearrangement, 209

6-(4-Hydroxy-5-(hydroxymethyl)

tetrahydrofuran-2-yl)-2,8-dimethyl­ [1,2,4]triazolo[1,5-c]pyrimidin-5(6H)­ one, 178

3-Hydroxyindolines, 103

5-Hydroxymethylcytosine, Dimroth

rearrangement, 190

5-Hydroxymethyl-2-deoxycytidine,

cleavage of glyscosidic bond in mass

spectra, 191

3-Hydroxymethylindole, electrochemical

oxidation, 114

2-Hydroxy-6-methylpyridine, reaction with

hydrated cupric nitrate, 27

6-Hydroxy-4-oxo-[1,2,3]thiadiazolo[4,5-c]­ pyridines, 188

2-Hydroxypyrimidine, 53

Imidazoisoquinolin-5-ones, 139

Imidazo[1,2-b]isoxazole, 156

Imidazol-5-carboxyamidines, 204

Imidazolidino[1,5-a]piprazin-4-one, 214

2-Imidazoline, 126

2-Imidazoline nitrone salt, 156

Imidazolinium N-oxides, 140, 156

Imidazolinium ylides, 140

Imidazo[1,2-a]pyridines, 132

Imidazopyridin-5-ones, 135, 139

7-Imino-5-phenyl-1,2,4-triazolo[1,5-a]­ pyrimidine, 173

Indigo, 111

Indole, 83

electrochemical oxidation, 114

reaction with 2-nitroindoles, 109

reaction with 3-bromoindole, 106

reaction with isatin, 108

reaction with sulphur, 112

Indole-3-carboxylates, 83

Indolocarbazole, 99, 110, 116, 117

3,30 -Indoloquinones, formation by

oxidative cyclization, 102

6-(3-Indolyl)benzo[b]carbazole, 103

11-(3-Indolyl)benzo[b]carbazole, 103

Indolyl-3-boronic acid, Suzuki–Miyaura

coupling with 1-iodocarbazoles, 110

Indolyl Grignard reagents, coupling with

iodoindoles, 109

2,20 -Indolyl-indoline, 105

Indolyl-2-nitrostyrenes, reductive

cyclization, 101

3-Indolylzinc compounds, coupling with

3-bromoindoles, 109

Indoxyl, oxidation to indigo, 111

Intramolecular carboalkoxylation of

alkynes, 82

Inulin, fragmentation by inulin

fructotransferase, 19

3-Iodo-2,20 -biindolyl, palladium catalysed

benzannulation, 117

2-Iodoindoles, coupling with borate esters,

109

bis(3-Iodophenyl)porphyrin, reaction with

bis(4-ethynylphenyl)porphyrin, 13

Isatin, reaction with indole, 108

Isochromones-1-ones, 79

1-Isopropyladenine, 199

15

N4-Labeled cytidine-N3-oxide, with

benzyl bromide, 192, 200

15 4 N -Labeled 2-deoxycytidine-N3- oxide,

reaction with benzyl bromide, 200

15 3 N -Labeled uridine, 191

Subject Index

15

N4-Labeled uridine 4-O-benzyloxime,

192, 200

Leucoindigo sodium salt, 111

Light-harvesting complexes in

photosynthetic purple bacteria,

structure, 14

Linear maltooligosaccharides, 56

Lysidine, 129

N5,N10-Methenyltetrahydrofolate, 126

4-Methoxy (aralkoxy)iminobenzo[1,3]

oxazine-2-ones, 213

2-Methoxynaphthoquinone, reaction with

N-methyltryptamine, 102

6-N-Methoxy nucleosides, 202

N-[1-(4-Methoxyphenyl)-1H-tetrazol-5-yl]­ aniline, 220

3-Methyladenosine, 207

6-Methyladenosine, 207

1-Methyladenosine adduct, Dimroth

rearrangement, 206

2,6-bis(Methylamino)pyridine, Pd­ catalyzed reaction with 2,6­ dibromopyridine, 36

5-Methylbenzene-1,3-dialdehyde, reaction

with excess 2-acetylpyridine, 42

N-Methylbenzimidazole, 146

Methyl bromoacetate, as an alkylating

agent, 144

Methyl (E)-but-2-enoate as a dipolarophile, 143

Methyl but-2-enoate, as a dipolarophile in

placing substituents at C—6 of

pyrroloimidazoles, 153

2-Methyl-N-tert-butyloxycarbonyl

imidazoline, 130

[N1-Methyl-50 ­ deoxyadenosylcobaltamine]Cl,

Dimroth rearrangement, 205

N6-Methyl-deoxyadenosylcobaltamine, 205

3-Methyl-4,6-dialkylprid-2-one, 188

Methyl 5,6-dimethoxyindole-2-carboxylate,

reaction with 2-indolinone and

phosphoryl chloride, 108

N5-Methyl-FH4, 127

N-Methylformamidoimidazole, 207

N-Methylformanilides, reaction with

phosphoryl chloride, 99

9-Methylguanine, 64

2-Methyl-2-imidazoline, double

deprotonation, 128

double alkylation, 130

lateral metallation, 129

235

2-Methylimidazolines, reaction with

N-phenylmaleimides, 147

5-(1-Methylimidazol-2-yl)-10,15-bis(3­ allyloxypropyl)-20-(3-formylphenyl)­ porphyrin, condensation with meso­ methoxycarbonyldipyrromethane, 16

N-Methyl-4-phenyl-2-imidazolines, 151

5-Methyl-3-phenylpyrazole, in

metallomacrocycles, 21

2-Methylpropenonitrile, 153

1-Methyl-3,3a,4,5-tetrahydroimidazo[1,5-a]­ isoquinoline C-2(�) metallation, 131

3-Methyl-1,5,6,10b-tetrahydroimidazo[5,1­ a]isoquinoline, C-2(�) metallation, 131

N-Methyltryptamine, reaction with 2­ methoxynaphthoquinone, 102

Modified oligonucleotides, Dimroth

rearrangements, 207

Monoacetoxylated-2,20 -biindolyl, 111

5-(Neophenyl glycolatoboron)-500 -methyl­ 20 :60 200 -terpyridine, 59

Newkome’s hexameric

metallomacrocycles, 45

(2-Nitroethenyl)benzene, reaction with 2­ benzylimidazoline, 149

2-Nitrostyrenes, reductive cyclization, 101

Non-branched fractal polymer, 47

8-Oxadenosine, alkylation with 4­ benzyloxy-3,5-dibromobenzyl

bromide, 201

Oxalic acid-bis(imidoyl)dichloride, 184

2-Oxazolines, 127

5-Oxo-1,2,4-triazolo[4,3-c]pyrimidines,

isomerization to the oxo-1,2,4-triazolo­ [1,5-c]pyrimidines, 162

Oxymetazoline, 126

bisPalladium adducts of 1,2,4,5-tetrakis­ (n-butylthiomethyl)benzene, 54

bisPalladium adducts of 1,2,4,5-tetrakis­ (phenylthiomethyl)benzene, 54

Permethylated cycloinulohexaose, 21

4,7-Phenanthroline, as a bridging

ligand, 54

Phentolamine, 126

Phenylacetylene-modified terpyridine­ based macrocycles, 41

2-Phenyl-3-aminoimidazo[1,2-a]­ pyrimidines, rearrangement to 2­ amino-3-phenyl isomer, 169

236

Subject Index

4-(Phenylamino)quinazoline-2(1H)-selone,

210

2-Phenyl-2,30 -biindolyl, 106

5-Phenyldipyrromethane, 6

5,50 -m-Phenylene-bridged gable-porphyrin

with 15,150 -bis(imidazolyl) groups,

15

2-Phenyl-4-formylimidazole, reaction with

2-aminoethylpyridine, 60

Phenylglycine, N-protection as its

benzyloxycarbonyl (Z) derivative, 150

2-Phenyl-N-hydroxyindole, photo-

irradiation, 114

4-Phenyl-2-imidazolines, 150

N-(2-Phenylimidazol-4-ylmethylidene)-2­ aminoethylpyridine, as a ligand, 62

3-Phenyl-4-iminoquinazoline-2(1H)-selone,

formation and Dimroth

rearrangement, 210

2-Phenylindole, reaction with 2-indolinone

and phosphoryl chloride, 106

N-Phenyl-4-phenyl-2-imidazolines, 151

1-(2-Phenylquinazolin-4-yl)-3-substituted

thioureas, formation by Dimroth

rearrangements, 211

N-Phenylsulfonyl-3-phenyl-4,6­ dimethoxyindole, oxidation by

thallium(III) trifluoroacetate, 112

Phosphonylated substituted isoindoles, 88

Pityriazole, 110

Platinum-catalyzed carboselenation

reactions, 91

Platinum-catalyzed intramolecular

carboamination of alkynes to

substituted indoles, 84

Poly(crown ether) hexamers, 27

Polydiacetylenes, 36

Poly[2]pseudorotaxanes, 27

Polypyrrole, 7

Porphyrin pentamer, reaction with a

porphyrin monomer, 14

Propargylic o-(alkynyl)phenyl ethers,

cyclization, 76

2-(Prop-2-enyl)-2-imidazoline, reaction

with but-2-enal, 138

reaction with but-3-yn-2-one, 138

2-i-Propyl-5-formyl-1,2,4-triazolo[1,5-a]­ pyridine, 172

3-i-Propyl-5-formyl-1,2,4-triazolo[4,3-a]­ pyridine, Dimroth rearrangement, 172

Protonated cytosine, Dimroth

rearrangement, 190

Purines, reaction with ethanolamine

followed by Dimroth rearrangement,

207

6-Purinethione ribose, 65

2H-Pyran-2-imine, 188

Pyrazolo[4,3-e][1,2,4] [1,5-c]pyrimidine

derivatives, 177

Pyrazolo-1,2,4-triazolo[4,3-c]pyrimidin­ 5(6H)-ones, Dimroth rearrangements,

175

Pyrazolo[3,4-d][1,2,3]triazolo[1,5-a]­ pyrimidines, 177

4-Pyridinecarboxaldehyde, reaction with

pyrrole, 63

3,5-bis(Pyridine-4-ylethynyl)phenol,

connection to crown ethers, 25

reaction with ferrocene-1-carboxylic

acid, 26

Pyridinophanes, 34

3-Pyridinylboronic acid, Suzuki coupling

with bromoaldehydes, 28

3{5}-(Pyridin-2-yl)-5-(t-butyl)pyrazole,

reaction with cupric fluoride, 64

bisPyridinyl ketone, in macrocycles, 25

Pyridoimidazole heterocumulenes,

thermolysis, 216

Pyridoimidazole-linked imidazolediones,

216

Pyrido[2,3-d]pyrimidines, 209

5-(4-Pyridyl)dipyrromethene, as a ligand,

63

3,8-bis(2-Pyridyl)-4,7-phenanthrolene,

55

2,4,6-tris-4-Pyridyl-s-triazine, in complexes,

9

4-Pyrimidinecarboxaldehyde, reaction with

2,3-bis(hydroxylamino)-2,3­ dimethylbutane, 62

4-Pyrimidinyl nitronyl nitroxide, as a

ligand, 62

Pyrimido[5,4-d]pyrimidines, 207

Pyrrole, reaction with 4­ quinolinecarboxaldehyde or

4-pyridinecarboxaldehyde, 63

Pyrrole rings in hexameric macrocycles, 6

Pyrrolidine-2-carboxamides, 154

Pyrrolidine-2,4-dicarboxylic acid

derivatives, 145

2,4-Pyrrolidine diesters, 154

Pyrrolo[1,2-a]imidazoles, 142, 157

Pyrrolo[1,2-a]pyrazines, 148

Pyrrolo[1,2,3-de]quinoxalines, 144, 156

Subject Index

Quaterpyridines, 40

Quinazolines, synthesis by Dimroth

rearrangements, 210

4-Quinolinecarboxaldehyde, reaction with

pyrrole, 63

5-(4-Quinolyl)dipyrromethene, as a ligand,

63

Quinquepyridines, 40

Rigid hexameric macrocycles, 11

“Ring opening, ring closing” (RORC)

processes, 162

Self-assembly of architectures mediated by

transition metals, review, 2

Self-assembly of macrocycles, 25

“Sexipyridine,” 29

conformations, 30

Shape-persistent hexagonal macrocycles,

49

“Sierpinski hexagonal gasket,” 47

Silicon-bridged heterocycles, 5

3-Silylbenzo[b]thiophenes, 90

Spiro{6H-indeno[20 ,10 :5,6]pyrano[2,3-d]­ pyrimidine-5,30 -indoline}, 213

Starch, degradation, 56

N(1)-Substituted

3-alkoxycarbonylpiperidines, 133

N(1)-Substituted

3-alkoxycarbonyltetrahydropyridines,

134

2-Substituted-3-allenylbenzo[b]furans, 77

2-Substituted 3-allylbenzo[b]furans, 77

4,5-Substituted 2-aminoimidazoles, 209

3-Substituted-2-aminoimidazo[1,2-a]

pyrimidines, regioselective synthesis,

169

C-3-Substituted benzofurans, 78

Substituted bisterpyridine-building blocks,

52

Substituted butenolides, 79

15 4 N -Substituted cytidine N3-oxide,

Dimroth rearrangement, 191

N3-Substituted-cytosine, Dimroth

rearrangement during acetylation,

191

1-Substituted deoxyadenosine-styrene

oxide adducts, Dimroth

rearrangements, 196

3-Substituted-4,6-dimethoxyindoles,

reaction with 2-indolinone and

phosphoryl chloride, 107

237

3-Substituted-7,9-diphenylpyrazolo[4,3-e]­ [1,2,4]triazolo[4,3-c]pyrimidines,

175

2-Substituted 6H-imidazo[1,2-c]quinazolin­ 5-ones, 171

3-Substituted 6H-imidazo[1,2-c]quinazolin­ 5-ones, Dimroth rearrangement, 171

3-Substituted indoles, 83

acid-catalysed dimerization, 105

Substituted indoles, synthesis, 84

Substituted isocoumarins, 79

3-Substituted 2-oxo-2H-1,2,4-triazino[2,3-c]­ quinazolines, 181

2-Substituted-3-propargylbenzo[b]furans,

77

N-Substituted pyrroles, 143

Substituted 3(5H)-pyrrolin-2-ones,

synthesis, 183

5-Substituted 1,3-[bis(2,20 :60 ,200 -terpyridin­ 40 -ylethynyl)]benzenes, 45

2-Substituted thieno[2,3-e][1,2,4]triazolo­ [1,5-c]pyrimidin-5(6H)-ones, 174

C-3-Substituted thiophenes, 90

3-Sulfonylindoles, 86

6-Sulfonylindoles, 86

Sulfur-bridged thiophene macrocycles, 5

Supramolecular chemistry, 2

Supramolecular tris[2]pseudorotaxane

hexamer, 25

Symmetry Interaction Model, 2

Template-free hexameric macrocycles, 16

7,7; 2,70 -Terindole, 113

2,30 ; 2,30 -Terindolyl, 106

2,70 ; 2,70 -Terindolyl, 108

Terindolyls, 115

Terpyridine-based macrocycles, 41

Terpyridine-based, Zn(II)-hexamer, 45

4,40 -bis(2,20 :60 200 -Terpyridinyl)

triphenylamine, 47

3,30 ,4,40 -Tetraalkylbipyrroles, 8

Tetrahydroimidazo[1,2-a]pyridines, 138

1,2,5,6-Tetrahydro-2-methylene-N,1­ diphenyl-4-pyridinamine, 190

Z-Tetrahydropyrrolo[1,2-a]imidazol-6­ ones, 140

Tetraindolyls, 115

Tetrakis((1H-1,2,3-triazol-5-amine)­ sulfonyl)calix[4]arenes, 217

Tetrapyrido[3,2-a:20 ,30 -c:300 , 200 -h:2000 ,3000 -j]­ phenazine, as a building

block, 56

238

Subject Index

1-(5-Tetrazolyl)-3,5-diaryl-D2-pyrazolines, 220 Thieno[2,3-e][1,2,4]triazolo[4,3-c]­ pyrimidin-5(6H)-one, instability and rearrangement to thieno[2,3-e]-[1,2,4]­ triazolo[1,5-c]pyrimidin-5(6H)-ones, 164 instability, 173 Thiophene rings in hexameric macrocycles, 4 2-Thio[1,2,4]triazolo[1,5-c]quinazoline, 178 Tjipanazole family, 102 Toroidal dodecahydrohexaazakekulene macrocycle, 33 1H-5-Tosylamino-1,2,3-triazole-4-N­ phenylcarboxamide, 217 N-Tosyl-3-indolecarbaldehyde, 102 Transition metal-catalyzed annulation of alkynes bearing heteroatoms, 76 Transmission electron microscopy of Fe(II) metallohexamers, 44 Traveling wave ion mobility mass spectrometry, in analysis of hexamers, 44 2,6-bis(Trialkyltin)pyridine, reaction with bromopyridines, 41 Triazepines, 220 N-(4-R-1H-1,2,3-Triazol-5-yl)-1,2,5­ oxadiazole-3,4-diamines, by Dimroth rearrangement, 219 Triazolo[1,5-c]pyrimidines, from triazolo­ [4,3-c] isomers, 164 by Dimroth rearrangements of triazolo­ [4,3-c]pyrimidines, 175 Triazolopyrimidinones, 178

1,2,4-Triazolo[1,5-c]pyrimidin-5(6H)-ones, 172 1,2,4-Triazolo[4,3-c]pyrimidin-5(6H)-ones, reaction with bases, 172 1,2,4-Triazolo[4,3-c]pyrimidinone nucleoside, 177 1,2,4-Triazolo[1,5-d][1,2,4]triazin-5(6H)­ ones, 180 Tricyclic 1,2,4-triazolopurin-5(6H)-ones, Dimroth rearrangements, 175 7-(Trifluoromethyl)imidazo[1,2-a]­ pyrimidine, coupling with arylhalides, 171 3,6,10-Triphenyl-tris[1,2,4]triazolo[1,5­ a:10 ,50 -c:400 ,300 -e][1,3,5]triazine, 23 Tripyrroline, 186 Tryptophol, 103 C-2(�)-Unactivated, N-unsubstituted 2-alkyl-2-imidazolines, 137 �,�-Unsaturated acyl imidazolides, 135 2-Unsubstituted 2-imidazolines, conversion into 1,3-dipoles, 140 3-Unsubstituted indoles, 83 reaction with 3-bromoindoles, 106 Vibsanol, 78 5-Ylidenepyrrol-2(5H)-ones, 185 bis(Zinc-imidazolylporphyrin) linked by a m-bis(ethynyl)phenylene spacer, 16 Zinc perchlorate, reaction with 5-methyl-3­ phenylpyrazole, 21